AU3629901A - Novel compounds - Google Patents

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Publication number
AU3629901A
AU3629901A AU36299/01A AU3629901A AU3629901A AU 3629901 A AU3629901 A AU 3629901A AU 36299/01 A AU36299/01 A AU 36299/01A AU 3629901 A AU3629901 A AU 3629901A AU 3629901 A AU3629901 A AU 3629901A
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AU
Australia
Prior art keywords
phenyl
phenoxy
hydroxy
acetamide
propoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
AU36299/01A
Other versions
AU783496B2 (en
Inventor
Michael Bodkin
Tomas Eriksson
Peter Hansen
Martin Hemmerling
Krister Henriksson
Tomas Klingstedt
Lars Pettersson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
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AstraZeneca AB
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Publication date
Priority claimed from SE0000620A external-priority patent/SE0000620D0/en
Priority claimed from SE0002234A external-priority patent/SE0002234D0/en
Priority claimed from SE0003979A external-priority patent/SE0003979D0/en
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of AU3629901A publication Critical patent/AU3629901A/en
Application granted granted Critical
Publication of AU783496B2 publication Critical patent/AU783496B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Description

WO 01/62728 PCT/SEO1/00403 1 NOVEL COMPOUNDS The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. 5 US 5789402 describes certain indole deriatives which are said to be useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems, particularly those relating to the serotonin lA receptor and those relating to the uptake of serotonin. 10 Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved 15 four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity. 20 The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2). The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and 25 MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins la and 1 P (MIP-la and MIP-1 [). Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G prdtein-coupled receptors, among which are the receptors designated CCR1, CCR2, 30 CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, WO 01/62728 PCT/SEO1/00403 2 CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those previously mentioned. 5 In accordance with the present invention, there is therefore provided a compound of general formula R OH R Q 2 RRR R2 R R (1) 1o wherein, R represents either a group
(R
1 )m (R)" Z or a group H 1N (R')m 15 mis0, 1,2or3; each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C
3
-C
6 cycloalkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxycarbonyl, C 1
-C
6 haloalkyl,
CI-C
6 haloalkoxy, -NR 9
R'
0 , C 3
-C
6 cycloalkylamino, C 1
-C
6 alkylthio, 20 Ci-C 6 alkylcarbonyl, C 1
-C
6 alkylcarbonylamino, sulphonamido (-SO 2
NH
2 ), Ci-C 6 alkylsulphonyl, -C(O)NR1 R , -NR 13C(O)-(NH),R , phenyl, or C 1
-C
6 alkyl optionally substituted by carboxyl or Cl-C 6 alkoxycarbonyl; p is 0 or 1; WO 01/62728 PCT/SEO1/00403 3 X represents an oxygen or sulphur atom or a CH 2 , CH(CH 3 ), OCH 2 , CH 2 0, CH 2 NH, NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH 2 0, CH 2 NH or NH group, then Y represents a CH group; 5 ZI represents a bond or a group (CH2)q where q is 1 or 2; Z2 represents a bond or a group CH 2 , with the proviso that Z and Z2 do not both simultaneously represent a bond; Q represents an oxygen or sulphur atom or a group CH 2 or NH; R2 represents a group 10 0 R 15 HN H3C N 16 (R4) 0 HN CH 3 0 HN
CH
3
HC
1 ~N or H3C N= H nis0, 1 or2; each R3 independently represents a Ci-C 6 alkyl, C 1
-C
6 alkoxycarbonyl, -CH 2 OH or 15 carboxyl group; R', R 5, R6 and R each independently represent a hydrogen atom or a CI-C 6 alkyl group, or R , Rs, R6 and R together represent a Ci-C 4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, WO 01/62728 PCT/SEO1/00403 4 5 6 7 4 8 or R , R and R each represent a hydrogen atom and R and R together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R
8 represents a hydrogen atom, a CI-C 6 alkyl group or is linked to R4 as defined above; s R 9 and R 10 each independently represent a hydrogen atom or a Ci-C 6 alkyl group, or R9 and R together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; RI I and R12 each independently represent a hydrogen atom or a C 1
-C
6 alkyl group optionally substituted by CI-C 6 alkoxycarbonyl; 10 R13 represents a hydrogen atom or a CI-C 6 alkyl group; R14 represents a hydrogen atom, or a CI-C 6 alkyl group optionally substituted by carboxyl, C 1
-C
6 alkoxy or C 1
-C
6 alkoxycarbonyl; R i represents carboxyl, Ci-C 6 alkylcarbonyl, CI-C 6 alkoxycarbonyl,
C
1
-C
6 alkoxycarbonylCi-C 6 alkyl or a group -NR R is, -NHSO 2
CH
3 , -NHC(O)CH 3 , 17 18 17 18 17 18 17 18 is -C(O)NR R , -NHC(O)NR R , -OC(O)NR R , -OCH 2 C(O)NR R -NHC(O)OR 7 or -OR17" t is 0, 1, 2 or 3; each R16 independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C
3
-C
6 cycloalkyl, C 1
-C
6 alkoxy, Ci-C 6 alkoxycarbonyl, CI-C 6 haloalkyl, 20 Cl-C 6 haloalkoxy, -NR"R20, C 3
-C
6 cycloalkylamino, Ci-C 6 alkylthio,
C
1
-C
6 alkylcarbonyl, CI-C 6 alkylcarbonylamino, sulphonamido (-SO 2
NH
2 ), Ci-C 6 alkylsulphonyl, -C(O)NR21R , -NR23 C(O)(NH),R 24, phenyl, or C 1
-C
6 alkyl optionally substituted by carboxyl or Ci-C 6 alkoxycarbonyl; R and R18 each independently represent (i) a hydrogen atom, (ii) a 5- to 6 25 membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a Ci-C 6 alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, Ci-C 6 alkoxycarbonyl and a 5- to 6-membered 30 saturated or unsaturated ring which may comprise at least one heteroatom chosen from WO 01/62728 PCT/SEO1/00403 5 nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or R 1 and R18 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; s R 1 represents a hydrogen atom, or a CI-C 6 alkyl group optionally substituted by carboxyl or CI-C 6 alkoxycarbonyl; R171 is defined as for R above except that R does not represent a hydrogen atom; R19 and R20 each independently represent a hydrogen atom or a CI-C 6 alkyl group, or R19 and R20 together with the nitrogen atom to which they are attached form a 4- to 7 10 membered saturated heterocycle; R2 and R each independently represent a hydrogen atom or a CI-C 6 alkyl group optionally substituted by C 1
-C
6 alkoxycarbonyl; v is 0 or 1; R represents a hydrogen atom or a CI-C 6 alkyl group; and 15 R24 represents a hydrogen atom, or a CI-C 6 alkyl group optionally substituted by carboxyl, CI-C 6 alkoxy or CI-C 6 alkoxycarbonyl; provided that when X is an oxygen atom or a group CH 2 , Y is CH, ZI and Z2 each 2 represent a group CH 2 and Q is an oxygen atom, then R is other than an unsubstituted indolyl group; 20 or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. 25 In one aspect of the present invention, there is provided a compound of general formula WO 01/62728 PCT/SEO1/00403 6 R OH RQ 2 R 5 R R R R 6 wherein, R represents a group 3
(R
1 )m z I. s m is 0, 1, 2 or 3; each RI independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C
3
-C
6 cycloalkyl, C 1
-C
6 alkoxy, Ci-C 6 alkoxycarbonyl, Ci-C 6 haloalkyl,
C
1
-C
6 haloalkoxy, -NR 9
R
10 , C 3
-C
6 cycloalkylamino, C 1
-C
6 alkylthio,
CI-C
6 alkylcarbonyl, Ci-C 6 alkylcarbonylamino, sulphonamido, Ci-C 6 alkylsulphonyl, 10 -C(O)NR R 12, -NR 13C(O)-(NH),R 14, phenyl, or Ci-C 6 alkyl optionally substituted by carboxyl or CI-C 6 alkoxycarbonyl; p is 0 or 1; X represents an oxygen or sulphur atom or a CH 2 , CH(CH 3 ), OCH 2 , CH 2 0, CH 2 NH, NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided 15 that when X represents an oxygen or sulphur atom or a CH 2 0, CH 2 NH or NH group, then Y represents a CH group; Z represents a bond or a group (CH2)q where q is 1 or 2; Z2 represents a bond or a group CH 2 , with the proviso that ZI and Z2 do not both simultaneously represent a bond; 20 Q represents an oxygen or sulphur atom or a group CH 2 or NH; R2 represents a group R 16 (R )t WO 01/62728 PCT/SEO1/00403 7 n is 0, 1 or 2; each R3 independently represents a C 1
-C
6 alkyl, CI-C 6 alkoxycarbonyl, -CH 2 OH or carboxyl group; 5 R 4 , R', R 6 and R 7 each independently represent a hydrogen atom or a C 1
-C
6 alkyl group, or R , R', R6 and R' together represent a C 1
-C
4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R 5, R6 and R each represent a hydrogen atom and R4 and R8 together with the-carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle; 10 R represents a hydrogen atom, a Ci-C 6 alkyl group or is linked to R4 as defined above; R9 and R each independently represent a hydrogen atom or a C 1
-C
6 alkyl group, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; is RII and R12 each independently represent a hydrogen atom or a C 1
-C
6 alkyl group optionally substituted by CI-C 6 alkoxycarbonyl; R13 represents a hydrogen atom or a C-C 6 alkyl group; R represents a hydrogen atom, or a Ci-C 6 alkyl group optionally substituted by carboxyl, Ci-C 6 alkoxy or CI-C 6 alkoxycarbonyl; 20 R 15 represents carboxyl, Ci-C 6 alkylcarbonyl, Ci-C 6 alkoxycarbonyl,
C
1
-C
6 alkoxycarbonylCi-C 6 alkyl or a group -NR1 7
R
18 , -NHSO 2
CH
3 , -NHC(O)CH 3 , -C(O)NR R 18, -NHC(O)NR R 8, -OC(O)NR 1 R", -OCH 2 C(O)NRIR 1, -NHC(O)OR 7 or -OR 1"; t is 0, 1, 2 or 3; 25 each R16 independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C
3
-C
6 cycloalkyl, C 1
-C
6 alkoxy, C 1
-C
6 alkoxycarbonyl, C 1
-C
6 haloalkyl,
C
1
-C
6 haloalkoxy, -NR9R20, C 3
-C
6 cycloalkylamino, CI-C 6 alkylthio,
CI-C
6 alkylcarbonyl, C 1
-C
6 alkylcarbonylamino, sulphonamido (-SO 2
NH
2 ), Ci-C 6 alkylsulphonyl, -C(O)NR 1R2, -NR C(O)(NH)vR24, phenyl, or Ci-C 6 alkyl 30 optionally substituted by carboxyl or Ci-C 6 alkoxycarbonyl; WO 01/62728 PCT/SEO1/00403 8 R 1 and R each independently represent (i) a hydrogen atom, (ii) a 5- to 6 membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or 5' (iii) a CI-C 6 alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C 1
-C
6 alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or 10 R 7 and R18 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; R 7 represents a hydrogen atom, or a CI-C 6 alkyl group optionally substituted by carboxyl or CI-C 6 alkoxycarbonyl;
R
17 is defined as for R 17 above except that R does not represent a hydrogen atom; is R19 and R20 each independently represent a hydrogen atom or a CI-C 6 alkyl group, or R19 and R20 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; R and R each independently represent a hydrogen atom or a CI-C 6 alkyl group optionally substituted by C 1
-C
6 alkoxycarbonyl; 20 v is 0 or 1; R represents a hydrogen atom or a Ci-C 6 alkyl group; and R24 represents a hydrogen atom, or a Ci-C 6 alkyl group optionally substituted by carboxyl, CI-C 6 alkoxy or C 1
-C
6 alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof. 25 In another aspect of the invention, there is provided a compound of general formula R8 OH R R R2 R R FR ) WO 01/62728 PCT/SEO1/00403 9 wherein, R represents a group
(R
1 )m z R) . m is 0, 1, 2 or 3; 5 each RI independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C
3
-C
6 cycloalkyl, C 1
-C
6 alkoxy, C 1
-C
6 alkoxycarbonyl, CI-C 6 haloalkyl,
C
1
-C
6 haloalkoxy, -NR R 0, C 3
-C
6 cycloalkylamino, Ci-C 6 alkylthio,
C
1
-C
6 alkylcarbonyl, Ci-C 6 alkylcarbonylamino, sulphonamido, CI-C 6 alkylsulphonyl, -C(O)NR R 12, -NR 13C(O)-(NH),R 4, phenyl, or CI-C 6 alkyl optionally substituted by 10 carboxyl or Ci-C 6 alkoxycarbonyl; p is 0 or 1; X represents an oxygen or sulphur atom or a CH 2 , CH(CH 3 ), OCH 2 , CH 2 0, CH 2 NH, NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH 2 0, CH 2 NH or NH group, then 15 Y represents a CH group; Z represents a bond or a group (CH2)q where q is 1 or 2; Z2 represents a bond or a group CH 2 , with the proviso that ZI and Z2 do not both simultaneously represent a bond; Q represents an oxygen or sulphur atom or a group CH 2 or NH; 20 R2 represents a group WO 01/62728 PCT/SEO1/00403 10 0 HN
H
3 C N 0 HN CH 3 0 HN
CH
3 H3C N H nis0, 1 or2; each R3 independently represents a Ci-C 6 alkyl, C 1
-C
6 alkoxycarbonyl, -CH 2 OH or 5 carboxyl group; R4, R5, R6 and R each independently represent a hydrogen atom or a C 1
-C
6 alkyl group, or R , Rs, R6 and R together represent a Ci-C 4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, 5 6 7 4 8 or R , R and R each represent a hydrogen atom and R and R together with the carbon 1o atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R
8 represents a hydrogen atom, a CI-C 6 alkyl group or is linked to R4 as defined above; R9 and R each independently represent a hydrogen atom or a C 1
-C
6 alkyl group, or
R
9 and R together with the nitrogen atom to which they are attached form a 4- to 7 15 membered saturated heterocycle; R 1 and R12 each independently represent a hydrogen atom or a CI-C 6 alkyl group optionally substituted by C-C 6 alkoxycarbonyl; R13 represents a hydrogen atom or a C 1
-C
6 alkyl group; and WO 01/62728 PCT/SEO1/00403 11 R14 represents a hydrogen atom, or a Ci-C 6 alkyl group optionally substituted by carboxyl, C 1 rC 6 alkoxy or C 1
-C
6 alkoxycarbonyl; provided that when X is an oxygen atom or a group CH 2 , Y is CH, Z I and Z2 each represent a group CH 2 and Q is an oxygen atom, then R2 is other than an unsubstituted 5 indolyl group; or a pharmaceutically acceptable salt or solvate thereof. In a further aspect of the invention, there is provided a compound of general formula R 8 OH R R R2 10 R R (it,) wherein, R represents a group H (R)m 15 mis0,1,2or3; each RI independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C
3
-C
6 cycloalkyl, C 1
-C
6 alkoxy, C 1
-C
6 alkoxycarbonyl, C-C 6 haloalkyl,
C
1
-C
6 haloalkoxy, -NR 9 R1 0 , C 3
-C
6 cycloalkylamino, Ci-C 6 alkylthio,
C
1
-C
6 alkylcarbonyl, C 1
-C
6 alkylcarbonylamino, sulphonamido, Ci-C 6 alkylsulphonyl, 20 -C(O)NR R 12, -NR 3C(O)-(NH),R , phenyl, or Ci-C 6 alkyl optionally substituted by carboxyl or CI-C 6 alkoxycarbonyl; p is 0 or 1; Q represents an oxygen or sulphur atom or a group CH 2 or NH; R2 represents a group 25 WO 01/62728 PCT/SEO1/00403 12 0 R 15 HN H3C N (R ) 0 HN CH 3 0 HN
CH
3 or
H
3 C N H R , R5, R6 and R each independently represent a hydrogen atom or a Ci-C 6 alkyl group, or R4, R 5, R6 and R7 together represent a C 1
-C
4 alkylene chain linking the two 5 carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R , R6 and R each represent a hydrogen atom and R4 and R together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R
8 represents a hydrogen atom, a Ci-C 6 alkyl group or is linked to R4 as defined above; 10 R9 and R each independently represent a hydrogen atom or a Ci-C 6 alkyl group, or
R
9 and R together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; R 11 and R12 each independently represent a hydrogen atom or a C 1
-C
6 alkyl group optionally substituted by C 1
-C
6 alkoxycarbonyl; is R13 represents a hydrogen atom or a C 1
-C
6 alkyl group;
R
14 represents a hydrogen atom, or a C 1
-C
6 alkyl group optionally substituted by carboxyl, Ci-C 6 alkoxy or C 1
-C
6 alkoxycarbonyl; R1 5 represents carboxyl, Ci-C 6 alkylcarbonyl, Ci-C 6 alkoxycarbonyl,
CI-C
6 alkoxycarbonylCi-C 6 alkyl or a group -NR7 R 18, -NHSO 2
CH
3 , -NHC(O)CH 3
,
WO 01/62728 PCT/SEO1/00403 13 17 18 17 1817 18 17 18 -C(O)NR R8, -NHC(O)NR R1, -OC(O)NR R1, -OCH 2 C(O)NR R -NHC(O)OR 7 or -OR 1" t is 0, 1, 2 or 3; each R16 independently represents halogen, cyano, nitro, carboxyl, hydroxyl, S C 3
-C
6 cycloalkyl, CI-C 6 alkoxy, CI-C 6 alkoxycarbonyl, CI-C 6 haloalkyl,
CI-C
6 haloalkoxy, -NR9 R 20, C 3
-C
6 cycloalkylamino, Cl-C 6 alkylthio,
CI-C
6 alkylcarbonyl, Ci-C 6 alkylcarbonylamino, sulphonamido (-SO 2 NH2), 21 22 234
CI-C
6 alkylsulphonyl, -C(O)NR R , -NR C(O)(NH),R24, phenyl, or C 1
-C
6 alkyl optionally substituted by carboxyl or C 1
-C
6 alkoxycarbonyl; 10 R 17 and R 18 each independently represent (i) a hydrogen atom, (ii) a 5- to 6 membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a Ci-C 6 alkyl group optionally substituted by at least one substituent selected from 15 halogen, trifluoromethyl, carboxyl, C 1
-C
6 alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatoim chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or R 1 and R together with the nitrogen atom to which they are attached form a 4- to 7 20 membered saturated heterocycle; R 17 represents a hydrogen atom, or a C 1
-C
6 alkyl group optionally substituted by carboxyl or Ci-C 6 alkoxycarbonyl; R 7 is defined as for R above except that R does not represent a hydrogen atom; R 9 and R20 each independently represent a hydrogen atom or a Ci-C 6 alkyl group, or 25 R and R20 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; R21 and R each independently represent a hydrogen atom or a C 1
-C
6 alkyl group optionally substituted by CI-C 6 alkoxycarbonyl; v is 0 or 1; 30 R represents a hydrogen atom or a CI-C 6 alkyl group; and WO 01/62728 PCT/SEO1/00403 14 R24 represents a hydrogen atom, or a CI-C 6 alkyl group optionally substituted by carboxyl, CI-C 6 alkoxy or C 1
-C
6 alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof. 5 The integer m is preferably 0, 1 or 2. Each RI independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C 3
-C
6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), Ci-C 6 , preferably CI-C 4 , alkoxy (e.g. methoxy, ethoxy, n-propoxy or 10 n-butoxy), Ci-C 6 , preferably C 1
-C
4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), CI-C 6 , preferably C 1
-C
4 , haloalkyl (e.g. trifluoromethyl),
CI-C
6 , preferably CI-C 4 , haloalkoxy (e.g. trifluoromethoxy), -NR 9
R
10
C
3
-C
6 cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), Ci-C 6 , preferably CI-C 4 , alkylthio (e.g. methylthio or ethylthio), is Ci-C 6 , preferably Ci-C 4 , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), Ci-C 6 , preferably Ci-C 4 , alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido, Ci-C 6 , preferably Ci-C 4 , alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, 20 n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or 11 12 13 14 n-hexylsulphonyl), -C(O)NR R , -NR C(O)-(NH),R , phenyl, or
C
1
-C
6 , preferably Ci-C 4 , alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or Ci-C 6 , preferably Ci-C 4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). 25 Most preferably, each R independently represents halogen (particularly chlorine or fluorine), cyano, nitro, C 1
-C
6 alkoxy (especially methoxy), CI-C 6 alkylcarbonyl (especially methylcarbonyl) or CI-C 6 alkylcarbonylamino (particularly methylcarbonylamino). 30 WO 01/62728 PCT/SEO1/00403 15 Preferably X represents an oxygen atom or a CH 2 , OCH 2 , CH 2 0, NH or carbonyl group. Preferably Y represents a nitrogen atom or CH group. 5 Preferred combinations of X - Y include 0 - CH, OCH 2 - CH, NH - CH, CH 2 0 - CH,
CH
2 - N, C(O) - N and CH 2 - CH. Preferred combinations of Y, ZI and Z2 include: Y zi z2 CH CH 2 bond CH bond CH 2 CH CH 2
CH
2 CH (CH 2
)
2 bond N CH 2
CH
2 10 Q preferably represents an oxygen atom. Each R3 independently represents a C 1
-C
6 , preferably Ci-C 4 , alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), Ci-C 6 , preferably 1s CI-C 4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), -CH 2 OH or carboxyl group. It is preferred that R 3 represents a methyl, methoxycarbonyl, ethoxycarbonyl,
-CH
2 OH or carboxyl group. R , R 5, R6 and R each independently represent a hydrogen atom or a CI-C 6 , preferably 20 CI-C 4 , alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R 4 , R 5 , R 6 and R together represent a C 1
-C
4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle (e.g. cyclohexyl or preferably cyclopentyl), or R 5, R6 and R each represent a hydrogen WO 01/62728 PCT/SEO1/00403 16 atom and R 4 and R8 together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle (preferably cyclopentyl).
R
8 represents a hydrogen atom, a CI-C 6 , preferably C-C 4 , alkyl group (e.g. methyl, ethyl, 5 n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to Ri as defined above.
R
9 and R 10 each independently represent a hydrogen atom or a C-C 6 , preferably
C-C
4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 10 n-pentyl or n-hexyl), or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl). RII and R12 each independently represent a hydrogen atom or a Ci-C 6 , preferably 15 C-C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C 1
-C
6 , preferably C-C 4 , alkoxycarbonyl substituent group. R represents a hydrogen atom or a CI-C 6 , preferably C 1
-C
4 , alkyl group (e.g. methyl, 20 ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl). R14 represents a hydrogen atom, or a C-C 6 , preferably Cl-C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl, C 1
-C
6 , preferably C-C 4 , alkoxy or C 1
-C
6 , preferably 25 C-C 4 , alkoxycarbonyl. R15 represents carboxyl, Ci-C 6 , preferably C-C 4 , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C-C 6 , preferably CI-C 4 , alkoxycarbonyl (e.g. methoxycarbonyl or 30 ethoxycarbonyl), Cr-C 6 alkoxycarbonylCi-C 6 alkyl, preferably WO 01/62728 PCT/SEO1/00403 17
CI-C
4 alkoxycarbonylC I-C 4 alkyl (e.g. methoxycarbonylmethyl or methoxycarbonylethyl), 17 18 17 18 17 1 or a group -NR R , -NHSO 2
CH
3 , -NHC(O)CH 3 , -C(O)NR R , -NHC(O)NR R", -OC(O)NR R 18, -OCH 2 C(0)NR R 18, -NHC(O)OR or -OR". 5 It is preferred that R 15 represents C 1
-C
4 alkoxy (especially methoxy), C 1
-C
4 alkylcarbonyl (especially methylcarbonyl or ethylcarbonyl), C 1
-C
4 alkoxycarbonylCl-C 4 alkyl (particularly methoxycarbonylmethyl or methoxycarbonylethyl), -NHC(O)CH 3 , 17 18 17 18 -C(O)NR R , -NHSO 2
CH
3 or -NHC(O)NR R 16. to Each R independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C 3
-C
6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), Ci-C 6 , preferably Ci-C 4 , alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), Ci-C 6 , preferably C 1
-C
4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), Ci-C 6 , preferably C 1
-C
4 , haloalkyl (e.g. trifluoromethyl), 19 20 15 Ci-C 6 , preferably Ci-C 4 , haloalkoxy (e.g. trifluoromethoxy), -NR R
C
3
-C
6 cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C 1
-C
6 , preferably Ci-C 4 , alkylthio (e.g. methylthio or ethylthio),
C
1
-C
6 , preferably C 1
-C
4 , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or 20 n-hexylcarbonyl), C 1
-C
6 , preferably Ci-C 4 , alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,
C
1
-C
6 , preferably C-C 4 , alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR 21R, -NR23 C(O)-(NH),R 4, phenyl, or 25 Ci-C 6 , preferably Cl-C 4 , alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or Ci-C 6 , preferably
CI-C
4 , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
WO 01/62728 PCT/SEO1/00403 18 Preferably, each R16 independently represents halogen (particularly chlorine or fluorine), hydroxyl, cyano, CI-C 4 alkoxy (especially methoxy), CI-C 4 alkoxycarbonyl (especially methoxycarbonyl), CI-C 4 haloalkyl (especially trifluoromethyl), CI-C 4 alkylcarbonyl (particularly methylcarbonyl), phenyl or Ci-C 4 alkyl (e.g. methyl or tert-butyl). 5 R 1 and R18 each independently represent (i) a hydrogen atom, (ii) a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom (e.g. one, two or three heteroatoms independently) chosen from nitrogen, oxygen and sulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, 1o pyrimidinyl, thienyl or furanyl), the ring being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), methyl and trifluoromethyl, or (iii) a C 1
-C
6 , preferably CI-C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least one is substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, carboxyl, Ci-C 6 , preferably Ci-C 4 , alkoxycarbonyl, especially methoxycarbonyl, and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom (e.g. one, two or three heteroatoms independently) chosen from nitrogen, 20 oxygen and sulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), the ring being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), methyl and trifluoromethyl, or 25 R and R together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl). R represents a hydrogen atom or a Ci-C 6 , preferably CI-C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally WO 01/62728 PCT/SEO1/00403 19 substituted by carboxyl or, more preferably, Ci-C 6 , preferably Ci-C 4 , alkoxycarbonyl, especially methoxycarbonyl, R19 and R20 each independently represent a hydrogen atom or a Ci-C 6 , preferably 5 CI-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R19 and R20 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl). 1o R21 and R each independently represent a hydrogen atom or a C 1
-C
6 , preferably
CI-C
4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a CI-C 6 , preferably CI-C 4 , alkoxycarbonyl substituent group. is R represents a hydrogen atom or a C 1
-C
6 , preferably CI-C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl). R24 represents a hydrogen atom, or a CI-C 6 , preferably CI-C 4 , alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally 20 substituted by carboxyl, C 1
-C
6 , preferably CI-C 4 , alkoxy or C 1
-C
6 , preferably
CI-C
4 , alkoxycarbonyl. Preferred compounds of the invention include: N-(2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl) 25 acetamide hydrochloride, N-(5-Chloro-2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy propoxy} -phenyl)-acetamide hydrochloride, N-(2-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl) acetamide, WO 01/62728 PCT/SEO1/00403 20 1-(2-Aminophenoxy)-3-[4-(3,4-dichlorophenoxy)- 1-piperidinyl]-2-propanol dihydrochloride, N-(2- {3-[3-(3,4-dichlorophenoxy)- 1 -pyrrolidinyl)-2-hydroxypropoxy} phenyl) acetamide hydrochloride, 5 2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoic acid methyl ester, 2-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester, N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2 10 hydroxycyclopentyl}oxy)phenyl]acetamide, N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2 hydroxycyclopentyl } oxy)phenyl] acetamide, N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2 hydroxycyclohexyl}oxy)phenyl]acetamide, i5 N-(5-Chloro-2-{3-[3 -(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(3-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5 methyl-phenyl)-acetamide, N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl 20 phenyl)-acetamide, N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro phenyl)-acetamide, 1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol, 1-(7-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl) 25 ethanone, N-(4-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3 yl)-acetanide, N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 21 N-(2- {3-{3-(3 I,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamide, N-(2- f{3-{3-(3 ,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 5 N-(5-Chloro-2- {3 -[3 -(4-chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(3-Acetyl-2- {3-[3 )-(4-chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl j-2-hydroxy-propoxy} -4-methyl 10 phenyl)-acetamide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, 1 -[3-(4-Chloro-phenoxy)-pyrrolidin- l-yl]-3-(1 H-indol-7-yloxy)-propa-2-o1, 1 -(7- {3-13-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -indol- 1l-yl) 15 ethanone, N -(4- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -biphenyl-3-yl) acetamide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4- fluoro phenyl)-acetamide, 20 N-(2- {3-[3 -(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamide, N-(2- {3-13-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide N-(5-Chloro-2- {3-[3J-(4-fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} 25 phenyl)-acetamide, N-(3-Acetyl-2- {3J-[3-(4-fluoro-phenoxy)-pyrrolidin- 1 -yl j-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, N-(2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 22 N-(5-Fluoro-2- {3 -[3 -(4-fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxyl phenyl)-acetamide, 1 -[3 -(4-Fluoro-phenoxy)-pyrrolidin- Il-yl]-3-(l H-indol-7-yloxy)-propan-2-ol, 1 -(7- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl ]-2-hydroxy-propoxy} -indol- Il-yl) 5 ethanone, N-(4- f{3-(3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -biphenyl-3-yl) acetamide, N-(4-Fluoro-2- {3'-[3-(4-fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, 10 N-(2- {3-[3-(4-Fluoro-phenoxy)-py-rrolidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamnide, N-(2- {3- [3-(4-Fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -phenyl) acetamide, N-(5-Chloro-2-f {3-[3-(3 ,4-difluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} 15 phenyl)-acetamide, N-(3-Acetyl-2- {3 -[3-(3 ),4-difluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, N-(2- { 3-[3 -(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, 20 N-(2- {3-[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, 1- [3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- l-yl]-3-(l H-indol-7-yloxy)-propan-2-ol, 1 -(7- f{3-[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -indol- Il-yl) ethanone, 25 N-(4- f{3-[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -biphenyl-3 yl)-acetamide, N-(2- {3-[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, N-(2- { 3-[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl 30 phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 23 N-(2- { 3-[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}l -phenyl) acetamide, N-(5-Chloro-2- f{3-[4-(3 ,4-dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, 5 N-(3-Acetyl-2- { 3-[4-(3 ,4-dichloro-phenoxy)-piperidin- Il-yl] -2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, N-(2- { 3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, N-(2- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5-fluoro 10 phenyl)-acetamide, 1 -(7- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -indol- 1 -yl) ethanone, N-(4- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -biphenyl-3 yl)-acetamide, 15 N-(2- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, N-(2- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamnide, N-(2- f{3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 20 acetamide, N-(5-Chloro-2- {3-[4-(4-chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamnide, N-(3-Acetyl-2- f{3-[4-(4-chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, 25 N-(2- f{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, N-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, 1 -(7- {3 -[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -indol- Il-yl) 30 ethanone, WO 01/62728 PCT/SEO1/00403 24 N-(4- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -biphenyl-3-yl) acetamide, N-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, 5 N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamide, N-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, N- {5-Chloro-2-[3-(8-chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy 10 propoxy]-phenyl}-acetamide, N- {3-Acetyl-2-[3-(8-chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy propoxy]-5-methyl-phenyl} -acetamide, N- {2-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4 methyl-phenyl}-acetamide, is N- {2-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5 fluoro-phenyl} -acetamide, 1-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(lH-indol-7-yloxy)-propan 2-ol, 1- {7-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy] 20 indol- 1-yl} -ethanone, N- {4-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy] biphenyl-3-yl}-acetamide, N- {2-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4 fluoro-phenyl} -acetamide, 25 N- {2-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5 methyl-phenyl}-acetamide, N- {2-[3-(8-Chloro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy] phenyl}-acetamide, N- {5-Chloro-2-[3-(8-fluoro- 1,3,4,5-tetrahydro-pyrido [4,3 -b]indol-2-yl)-2-hydroxy 30 propoxy]-phenyl}-acetamide, WO 01/62728 PCT/SEO1/00403 25 N- {3-Acetyl-2-[3-(8-fluoro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy propoxy]-5-methyl-phenyl} -acetamide, N- {2-[3-(8-Fluoro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4 methyl-phenyl} -acetamide, s N- {5-Fluoro-2-[3-(8-fluoro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yll-2-hydroxy propoxy]-phenyl} -acetamide, 1-(8-Fluoro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1 H-indol-7-yloxy)-propan 2-ol, 1- {7-[3-(8-Fluoro- 1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy] 10 indol- 1-yl} -ethanone, N- {4-[3-(8-Fluoro- 1,3,4,5-tetrahydro-pyrido [4,3 -b]indol-2-yl)-2-hydroxy-propoxy] biphenyl-3-yl} -acetamide, N- {4-Fluoro-2-[3-(8-fluoro- 1,3,4,5-tetrahydro-pyrido [4,3-b]indol-2-yl)-2-hydroxy propoxy]-phenyl} -acetamide, is N- {2-[3-(8-Fluoro- 1,3,4,5-tetrahydro-pyrido [4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5 methyl-phenyl} -acetamide, N- {2-[3-(8-Fluoro- 1,3,4,5-tetrahydro-pyrido [4,3-b]indol-2-yl)-2-hydroxy-propoxy] phenyl} -acetamide, N-(2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 20 acetamide, 3-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester, 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol, 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 25 2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propan-1-one, 1-(2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 30 ethanone, WO 01/62728 PCT/SEO1/00403 26 3-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 1-(2,6-Dimethoxy-phenoxy)-3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]-propan-2-ol, 1-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, s (2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino) acetic acid methyl ester, (2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-acetic acid methyl ester, 2-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino) 10 2-methyl-propionic acid methyl ester, 2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1 -(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone, is 1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan 1-one, 1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) ethanone, N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)-4 20 methylphenyl]acetamide, 3-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester, 1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, (2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} 25 benzoylamino)-acetic acid methyl ester, 2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide, 1-(2-f{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone, WO 01/62728 PCT/SEO1/00403 27 1-(2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy} -phenyl) propan-1-one, 1-(2- {3-[3 -(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, 5 N-(2- {3-[4-(3,4-dichloroanilino)- 1 -piperidinyl]-2-hydroxypropoxy} phenyl)acetamide, 3-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 1-[3-(4-Chloro-phenoxy)-pyrrolidin-1 -yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol, 1-(3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 0 (2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino) acetic acid, methyl ester, 2-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino) 2-methyl-propionic acid methyl ester, 2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl 15 benzamide, 1-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -6-methoxy phenyl)-ethanone, 1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl)-propan 1-one, 20 1-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, N-(2- {3-[3-(4-Cyano-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 3-(2- {3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 25 propionic acid methyl ester, (2- {3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester, 2- {3 -[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 30 4- {I -[ 2 -Hydroxy-3-(2-propionyl-phenoxy)-propyl]-pyrrolidin-3-yloxy} -benzonitrile, WO 01/62728 PCT/SEO1/00403 28 N-(2-{2-Hydroxy-3-(3-(4-methoxy-phenoxy)-pyrrolidin- 1 -yl]-propoxy} -phenyl) acetamide, N-(4-chloro-2-{3-[4-(3,4-dichloroanilino)- 1 -piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, 5 3-(2-{3-[13-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester, 1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, (2-{3-[3-.(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-acetic acid methyl ester, 1o 2-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester, 2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}-6-methoxy 15 phenyl)-ethanone, 1-(2-f{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) propan-1-one, 1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy}-phenyl) ethanone, 20 N-(2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) acetamide, 3-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1 -yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester, 2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy}-N,N-dimethyl 25 benzamide, 1-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy}-phenyl) propan-1-one, (2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester, WO 01/62728 PCT/SEO1/00403 29 N-(2- {3-[3-(3,4-Difluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy } phenyl)-acetamide, N-(2- {3- [4-(4-Fluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 5 3-(2- {3-[4-(4-Fluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl)-propionic acid methyl ester, 1-(2,6-Dimethoxy-phenoxy)-3-[4-(4-fluoro-phenoxy)-piperidin- 1 -yl]-propan-2-ol, 1-[4-(4-Fluoro-phenoxy)-piperidin- 1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 1-(2- {3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} -phenyl)-ethanone, 10 2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide, 1-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl)-propan 1-one, (2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) is acetic acid methyl ester, N-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 3-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester, 20 1-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 1-(2- {3-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, 2-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester, 25 2- {3-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N dimethyl-benzamide, 1-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -6 methoxy-phenyl)-ethanone, N-(2- {3-[4-(4-Acetylamino-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 30 acetamide, WO 01/62728 PCT/SEO1/00403 30 N-(4- {I -[3-(2-Acetyl-phenoxy)-2-hydroxy-propyl]-piperidin-4-yloxy} -phenyl) acetamide, N-(4-cyano-2-{3-[4-(3,4-dichloroanilino)-1 -piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, 5 3-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 1-[4-(4-Chloro-phenoxy)-piperidin- 1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, 10 2-(2-{3-[4-(4-Chloro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -benzoylamino)-2 methyl-propionic acid methyl ester, 2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-6-methoxy 15 phenyl)-ethanone, 1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl)-propan 1-one, (2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino) acetic acid methyl ester, 20 N-(2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 3-(2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 1-(2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 25 ethanone, 2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N dimethyl-benzamide, 1-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propan- 1-one, WO 01/62728 PCT/SEOI/00403 31 N-[2-( {( 1R,2R).-2-[4-(3 ,4-dichlorophenoxy)- 1 -piperidinyl]- 1 hydroxycyclopentyllmethoxy)phenyljlacetamide, Methyl (2S,4R)-1- {3-[2-(acetylamino)phenoxy]-2-hydroxypropyl} -4-[(4 chlorobenzyl)oxy]-2-pyrrolidinecarboxylate hydrochloride, 5 N-(2- {3-[4-(3 ,4-Dichloroanilino)-l1-piperidinyl]-2-hydroxypropoxy} -4 methylphenyl)acetamnide, N-(2- {3-[4-(4-Chloroanilino)- 1 -piperidinyllj-2-hydroxypropoxylphenyl)acetamide, N-(4-Chloro-2- {3-[4-(4-chloroanilino)-l1-piperidinyl]-2-hydroxypropoxy} phenyl) acetamide, 10 N-(2- {3-[4-(4-Chloroanilino)-l1-piperidinyl]-2-hydroxypropoxy} -4 cyanophenyl)acetamide, N-(2- {3-[4-(4-Chloroanilino)-l1-piperidinyl]-2-hydroxypropoxy} -4 methylphenyl)acetamide, N-(5-Chloro-2- {3-[4-(4-fluoroanilino)-l1-piperidinyl]-2 15 hydroxypropoxy} phenyl)acetamide, N-(5-Chloro-2- {3-[4-(3 ,4-difluoroanilino)-l1-piperidinyl]'-2 hydroxypropoxy} phenyl)acetamnide, N-(5-Cyano-2-{3 -[4-(4-fluoroanilino)-l1-piperidinyl]-2-hydroxypropoxy} phenyl)acetamnide, 20 N-(5-Cyano-2-{3-[4-(3,4-difluoroanilino)-1 -piperidinyl]-2 hydroxypropoxylphenyl)acetamide, N-(2- {3-[4-(4-Fluoroanilino)-lI-piperidinyl]-2-hydroxypropoxy} -4 methylphenyl)acetam-ide, N-(2- {3-[4-(3 ,4-Difluoroanilino)-l1-piperidinyl]-2-hydroxypropoxy} -4 25 methylphenyl)acetamide, N-(2- {3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-(R)-hydroxy-propoxy phenyl)acetamide, N-(2- {3-[3 S-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]l-2S-hydroxy-propoxy} -phenyl) acetamide hydrochloride, WO 01/62728 PCT/SEOI/00403 32 N-(2- f{3-[3 (R)-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-(S)-hydroxy-propoxy phenyl)acetamide, N-[5-Chloro-2-( { (2S)-3-[(3 S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl}I oxy)phenyllacetamnide, 5 N-[5-Chloro-2-(f (2R)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl}I oxy)phenyl]acetamide, N-[5-Chloro-2-( {(2S)-3-[(-' R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl}I oxy)phenyl]acetamide, N-[5-Chloro-2-(f (2R)-3-[(3 S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 10 hydroxypropyl}I oxy)phenyl7Jacetamide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4,5-difluoro phenyl)-acetamide, N- {5-Chloro-2-[2-hydroxy-3 -(3-phenoxy-pyrrolidin- 1 -yl)-propoxy]-phenyl } acetamide, 15 N-(5-Chloro-2- {2-hydroxy-3 -[3-(4-nitro-phenoxy)-pyrrolidin- 1 -yl]-propoxy} -phenyl) acetamide, N-(5-Acetyl-2- { 3-[3-(3 ,4-dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, 4-Acetylamnino-3 - { 3-[3-(3 ,4-dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} 20 benzoic acid methyl ester, N-(3- f{3-[3-(3 ,4-Dichloro-phenoxy)-py-rrolidin- 1 -yl]-2-hydroxy-propoxy} -naphthalen 2-yl)-acetamide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-cyano phenyl)-acetamide, 25 4-Acetylamino-3-{3 -[3-(4-chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} benzoic acid methyl ester, N-(3- f{3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy- propoxy} -naphthalen-2 yl)-acetamide, N-(5-Cyano-2- {3-[4-(3 ,4-dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} 30 phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 33 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5 trifluoromethyl-phenyl)-acetamide, N-(5-Chloro-2- {3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide trifluoroacetate, 5 N-(5-Acetyl-2-f{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide trifluoroacetate, N-(2-f{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl) methanesulfonamide, N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)- 1 -pyrrodinyl]-2-hydroxypropoxy] 10 phenyl)urea, 1-(3- {2-[(Aminocarbonyl)amino]phenoxy} -2-hydroxypropyl)-3-(4 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate, 1-(3-{2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4 dichlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate, is 1-(3-{2-[(Aminocarbonyl)amino]-4-chlorophenoxy}-2-hydroxypropyl)-3-(4 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate, N-(2- {3-[3-(4-Chlorophenoxy)- 1 -pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N ethylurea hydrochloride, N-(2-{3-[3-(4-Chlorophenoxy)-1 -pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N 20 methylurea hydrochloride, (2S,4S)-1- {3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl} -4-(4-chlorophenoxy)-2 pyrrolidinecarboxylic acid; compound with trifluoroacetic acid, Ethyl (2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4 dichlorophenoxy)-2-pyrrolidinecarboxylate; trifluoroacetic acid salt, 25 N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2 hydroxypropyl}oxy)phenyl]acetamide; trifluoroacetic acid salt, N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyll-2 hydroxypropyl}oxy)phenyl]acetamide; trifluoroacetic acid salt, N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2 30 methylpropoxy}phenyl)acetamide hydrochloride, WO 01/62728 PCT/SEO1/00403 34 N-(2-{(1S*,2R*,3S)-3 -[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy} -phenyl)-acetamide, N-(2- { (1R*,2R*,3S*)-3- [3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide, 5 N-(2- {(2R*,3R*)-3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-butoxy} phenyl)-acetamide, N-(2- {(1 S,2R*,3)-3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy cyclopentyloxy} -phenyl)-acetamide, N-(2-{(2R*,3S*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-butoxy} 10 phenyl)-acetamide, N-(2-(2R*,3R)-3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-butoxy} phenyl)-acetamide, N-(2-{(2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy} phenyl)-acetamide, is N-(2- {(1 S*,2R*,3S)-3 -[4-(3-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide, N-[5-Chloro-2-( {(1 S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)- 1 -piperidinyl]-2 hydroxycyclopentyl} oxy)phenyl]acetamide, N-[4-Fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)- 1 -piperidinyl]-2 20 hydroxycyclopentyl}oxy)phenyl]acetamide, N-(2- {3-[4-(3,4-Dichlorobenzyl)- 1 -piperazinyl]-2-hydroxypropoxy} -phenyl)acetamide dihydrochloride, N-(2- {3-[4-(3,4-Dichlorobenzyl)- 1 -piperazinyl]-2-hydroxypropoxy} -4 fluorophenyl)acetamide, 25 N-(2- {3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1 -piperazinyl]-2 hydroxypropoxy}phenyl)acetamide, N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)- 1 -piperazinyl]-2 hydroxypropoxy}phenyl)acetamide, N-(5-Chloro-2- {3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2 30 hydroxypropoxy}phenyl)acetamide, WO 01/62728 PCT/SEO1/00403 35 N-(2- { 3-[4-(3 ,4-Dichlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2-hydroxypropoxy} -4 methylphenyl)acetamide, N-(2- {1 -[4-(3 ,4-Dichlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2-hydroxypropoxy} -4 fluorophenyl)acetamide, 5 N-(2- {3 [(S *R*)..4-(3 ,4-Dichlorobenzyl)-2,5-dimethyl-l1-piperazinyl]-2 hydroxypropoxy} phenyl)acetamide, N-(2- {3 [(S *R*)-4(4-Cffiorobenzyl)-2,5-dimethyl-li-piperazinyl]-2 hydroxypropoxy} phenyl)acetamide, N-(5-Chloro-2- {3-[(S*R *)..4(3 ,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2 10 hydroxypropoxy} phenyl)acetamide, N-(5-Chloro-2- {3-[(S*R *)-4(4chlorobeny)25dmethypperany1..2 hydroxypropoxy} phenyl)acetamide, 1 -(5-Chloro-2- {3-[4-(4-chlorobenzoyl)- 1 -piperazinyl]-2-hydroxypropoxy} phenyl)- 1 ethanone, 15 N-(5-Cyano-2- {3-[(S*R *)..4.(3 ,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2 hydroxypropoxy} phenyl)acetamide, N-(2- {3-[(S*R *)-4(4-Cforobenzyl)-2,5-dimethylpiperazinyl]-2..hydroxypropoxy} -5 cyanophenyl)acetamide, N-(5-Chloro-2- {3-[4-(4-chlorobe nzyl)-l1-piperazinylll-2-hydroxypropoxy} 20 phenyl)acetamide, N-(4-Chloro-2- f{3-[4-(4-chlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2 hydroxypropoxylphenyl)acetam-ide, N-(2- f{3-[4-(4-Chlorobenzoyl)- 1 -piperazinyl]-2-hydroxypropoxy} -5 cyanophenyl)acetamnide, 25 N-(2-1 3-[4-(4-Cblorobenzoyl)- 1-piperazinyl]-2-hydroxypropoxy} -4 methylphenyl)acetamnide, N-[5-Chloro-2-( {( 1R,2S,3R)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2 hydroxycyclopentyl} oxy)phenyl]acetamnide, N- { 2-[(2S)-(3- {(3S)-3 -[(4-Chlorophenyl)oxy]- 1 -pyrrolidinyl} -2-hydroxypropyl)oxy] 30 4-fluorophenyl}I acetamnide, WO 01/62728 PCT/SEO1/00403 36 N-[2-({(2S)-3-[(3S)-3-(4-Chlorobenzyl)pyrrolidinyl]-2 hydroxypropyl} oxy)phenyl]acetamide hydrochloride, N-(5-Chloro-2-{3-[3 -(4-chloro-benzyl)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) acetamide trifluoroacetic acid salt, 5 N-(2-{3-[3-(4-Chlorophenoxy)- 1-pyrrolidinyl]-2-hydroxypropoxy}-4-methylphenyl) 1 -pyrrolidinecarboxamide trifluoroacetate, N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4 hydroxyphenyl)acetamide trifluoroacetate, N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4 10 fluorophenyl]acetamide trifluoroacetic acid salt, N-(2-(3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl)-2-hydroxy-propoxy)-4,6-difluoro phenyl)-acetamide hydrochloride, N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2 hydroxypropyl}oxy)-4-fluorophenyl]acetamide trifluoroacetic acid salt, is N-[2-({(2S)-3-[(3R)-3-(4-Chlorobenzyl)pyrrolidinyl]-2 hydroxypropyl} oxy)phenyl]acetamide hydrochloride, N-{2-[(2R)- (3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy] 4-fluorophenyl} acetamide, N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2 20 hydroxypropyl} oxy) phenyl]acetamide trifluoroacetic acid salt, N-{2-[(2S)-(3-{(3R)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy] 4-fluorophenyl} acetamide, N-(2-{3-[3 -(4-Chlorophenoxy)- 1 -pyrrolidinyl]-2-hydroxypropoxy} -4-methylphenyl) N,N-dimethylurea trifluoroacetate, 25 N-(2-f{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide, N-{2-[(3-f{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1 methylpropyl)oxy]phenyl } acetamide hydrochloride, N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4 methoxyphenyl)acetamide hydrochloride, WO 01/62728 PCT/SEO1/00403 37 N-(2-[3-(4-Chloro-benzyloxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl) acetamide trifluoroacetic acid salt, N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy} phenyl)-acetamide, 5 N-(2- {(IS,2R,3S)*-3-[(3S)-3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy}-5-chloro-phenyl)-acetamide (diastereomeric mixture), N-[2-({(2R,3S) *-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxybutyl}oxy)-4 methylphenyllacetamide (diastereomeric mixture), N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2 10 methylpropyl)oxy]-4-fluorophenyl} acetamide hydrochloride, N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy}-4-fluoro-phenyl)-acetamide (diastereomeric mixture), N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide, i5 N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(4-Cyano-2-f{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, N-(4-Hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 20 hydroxy-cyclopentyloxy}-phenyl)-acetamide (diastereomeric mixture), N-(4-Hydroxy-2- {(1S,2R,3S)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 hydroxy-cyclopentyloxy}-phenyl)-acetamide, N-(4-Hydroxy-2-{(1R,2S,3R)-3-[(35)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 hydroxy-cyclopentyloxy}-phenyl)-acetamide, 25 N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2 hydroxycyclopentyl}oxy)phenyl]acetaiide, N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2 hydroxycyclopentyl}oxy)phenyl]acetamide, N-[5-Chloro-2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2 30 hydroxycyclopentyl}oxy)phenyl]acetamide, WO 01/62728 PCT/SEO1/00403 38 N-f{5-Chloro-2-[((1S,2R,3S)*-3- { [1-(4-chlorobenzyl)-4-piperidinyl]amino } -2 hydroxycyclopentyl)oxy]phenyl} acetamide (racemic mixture), and N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4 hydroxyphenyl]acetamide. 5 The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises, (a) reacting a compound of general formula 10 R-H (II) wherein R is as defined in formula (I), with a compound of general formula 0 RQ R R R2 R 4 R 6yy wherein Q, R2, R4, R5, R6, R and R are as defined in formula (I); or is (b) reacting a compound of general formula R 0 R R R (IV) wherein R, R , R', R6, R and R' are as defined in formula (I), with a compound of general formula 20 LI - Q-R 2 (V) wherein LI represents a hydrogen atom or an activating group (e.g. Li when Q is CH 2 ) and Q and R2 are as defined in formula (I); WO 01/62728 PCT/SEO1/00403 39 and optionally thereafter converting the compound of formula (I) to a further compound of formula (I); and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I). 5 In one aspect, the invention provides a process for the preparation of a compound of formula (I') as hereinbefore defined which comprises, (a) reacting a compound of general formula R-H (II') wherein R is as defined in formula (I'), with a compound of general formula 10 0 R8 R R2 4 6 R R (III,) wherein Q, R2, R4, R , R , R and R8 are as defined in formula (I'); or (b) reacting a compound of general formula R 8 o S R R 15 R R (IV') wherein R, R4, R', R , R and R' are as defined in formula (I'), with a compound of general formula L1 - Q-R 2 (V') 20 wherein L I represents a hydrogen atom or an activating group (e.g. Li when Q is CH 2 ) and Q and R2 are as defined in formula (I'); and optionally thereafter converting the compound of formula (I') to a further compound of formula (I'); and, if desired, forming a pharmaceutically acceptable salt or solvate of the 25 compound of formula (I').
WO 01/62728 PCT/SEO1/00403 40 In another aspect, the invention provides a process for the preparation of a compound of formula (I") as hereinbefore defined which comprises, (a) reacting a compound of general formula R - H (II") s wherein R is as defined in formula (I"), with a compound of general formula O RQ R 6 R wherein Q, R2, R , R', R6, R and R8 are as defined in formula (I"); or (b) reacting a compound of general formula 10 R o R R R (5V ) wherein R, R4, R , R6, R and R' are as defined in formula (I"), with a compound of general formula 15 L1 - Q-R 2 (V") wherein LI represents a hydrogen atom or an activating group (e.g. Li when Q is CH 2 ) and Q and R2 are as defined in formula (I"); and optionally thereafter converting the compound of formula (I") to a further compound of 20 formula (I"); and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I"). In yet another aspect, the invention provides a process for the preparation of a compound of formula (I"') as hereinbefore defined which comprises, 25 (a) reacting a compound of general formula R - H (II"') WO 01/62728 PCT/SEO1/00403 41 wherein R is as defined in formula (I'"), with a compound of general formula 0 RQ S R 7 R2 R R 611, wherein Q, R2, R4, R 5, R 6, R and R8 are as defined in formula (I"'); or s (b) reacting a compound of general formula 8 R R R (W) 4 5 6 7 8 wherein R, R , R , R , R and R8 are as defined in formula (I"'), with a compound of general formula 10 L Q - R2 (V. wherein L I represents a hydrogen atom or an activating group (e.g. Li when Q is CH 2 ) and Q and R2 are as defined in formula (I."); is and optionally thereafter converting the compound of formula (I"') to a further compound of formula (I'"); and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I'"). The processes of the invention may conveniently be carried out in a solvent, e.g. an organic 20 solvent such as an alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene) or acetonitrile at a temperature of, for example, 15*C or above such as a temperature in the range from 20 to 120*C. Compounds of formulae (II), (II'), (II"), (II"'1), (II, (II), (III"), (III"'..), (IV), (IV', (IV"), 25 (IV"'), (V), (V'), (V") and (V.') are either commercially available, are well known in the literature or may be prepared easily using known techniques.
WO 01/62728 PCT/SEO1/00403 42 Compounds of formula (I), (I'), (I") or (I.') can be converted into further compounds of formula (I), (I'), (I") or (I.') using standard procedures. For example, a compound of formula (I) in which R 15 represents -NHC(O)CH 3 can be converted to a further compound 5 of formula (I) in which Ris represents -NH 2 by a hydrolysis reaction in the presence of hydrochloric acid. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting 10 reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I), (I'), (I") or (I.') may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective Groups in is Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley Interscience (1991). The compounds of formula (I), (I'), (I") or (I.') above may be converted to a 20 pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate. Compounds of formula (I), (I'), (I") or (I"') are capable of existing in stereoisomeric forms. 25 It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (I), (I'), (I") or (I"') and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.
WO 01/62728 PCT/SEO1/00403 43 The compounds of formula (I), (I'), (I") or (I"') have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially MIP- 1 cx chemokine receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of 5 transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS). Examples of these conditions are: (1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, 10 intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis 15 including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, 20 Sjogren's syndrome and systemic sclerosis; (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous 25 eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema; 30 WO 01/62728 PCT/SEO1/00403 44 (5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary 5 syndrome and idiopathic thrombocytopenia pupura; (6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; 10 (7) cancers, especially non-small cell lung cancer (NSCLC) and squamous sarcoma; (8) diseases in which angiogenesis is associated with raised CXCR2 chemokine levels (e.g. NSCLC); and 15 (9) cystic fibrosis, stroke, re-perfusion injury in the heart, brain, peripheral limbs and sepsis. Thus, the present invention provides a compound of formula (I), (I'), (I") or (I"'), or a 20 pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (I), (I'), (I") or (I."), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore 25 defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. 30 WO 01/62728 PCT/SEO1/00403 45 The invention also provides a method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), (I'), (I") or (I'".), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined. 5 The invention still further provides a method of treating an airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), (I'), (I") or (I'".), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined. 10 For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (1), (I'), (I") or (I"') may be in the range from 0.001 mg/kg to 30 mg/kg. 15 The compounds of formula (I), (I'), (I") or (I.') and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I), (I'), (I") or (I.') compound/salt/solvate (active ingredient) is in association with a pharmaceutically 20 acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. 25 The present invention also provides a pharmaceutical composition comprising a compound of formula (I), (I'), (I") or (I'"), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carter. 30 WO 01/62728 PCT/SEO1/00403 46 The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), (I'), (I") or (I'".), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier. 5 The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form 10 of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. The invention will now be further explained by reference to the following illustrative examples, in which 'H NMR spectra were recorded on Varian Unity Inova 400. The is central solvent peak of chloroform-d (5H 7.27 ppm) were used as internal standard. Low resolution mass spectra and accurate mass determination were recorded on a Hewlett Packard 1100 LC-MS system equipped with APCI /ESI ionisation chambers. All solvents and commercial reagents were laboratory grade and used as received. The nomenclature used for the compounds was generated with ACD/IUPAC Name Pro. 20 Example 1 N-(2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl) acetamide hydrochloride 25 (i) 3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of pyrrolidin-3-ol (16.25g, 186.5 mmol) and di-tert-butyl-dicarbonate (40.7g, 186.5 mmol) in dry THF (50 ml) under nitrogen was stirred over night. Concentration at reduced pressure and purification by flash chromatography on silica (EtOAc : heptane, 7 : 3) gave 31.9 g (91 %) of the subtitle compound. 30 WO 01/62728 PCT/SEO1/00403 47 'H-NMR (400MHz, DMSO-d6): 8 4.87 (d, 1H, J= 3.4 Hz), 4.21 (bs, 1H), 3.31-3.22 (m, 3H), 3.10 (d, 1H, J= 11.5 Hz), 1.83 (m, 1H), 1.72 (m, 1H), 1.39 (s, 9H). APCI-MS: m/z 132 [MH*-56] 5 (ii) 3-(4-Chloro-phenoxy)-pyrrolidine 3-Hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester (2.1g, 9.9 mmol) and triphenyl phosphine (2.59g, 9.9 mmol) were dissolved in dry THF (35 ml) under nitrogen. The solution was cooled to 0*C and 4-chlorophenol (1.28g, 9.9 mmol) dissolved in dry THF (10 ml) was added followed by diethyl azodicarboxylate (DEAD) (1.55 ml, 9.9 mmol). 10 After 15 minutes the ice bath was removed and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was stirred with ether. The solid triphenyl phosphine oxide was filtered off. The solution was washed three times with sodium hydroxide (IM) and concentrated. The BOC-protected product was purified by flash chromatography on silica using EtOAc/ heptane as eluant. It was 15 dissolved in dichloromethane (35 ml) and trifluoroacetic acid (17 ml). The reaction mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography on silica (MeOH:CHC1 3
:NH
3 , 100:100:1) to give the subtitle compound (1.72g, 88%). 20 'H-NMR (400MHz, DMSO-d6): 8 7.30 (d, 2H, J = 8.9 Hz), 6.91 (d, 2H, J= 8.9 Hz), 4.82 (m, 1H), 3.03 (dd, 1H, J = 12.3, 5.4 Hz), 2.82 (m, 3H), 1.99 (m, 1H), 1.72 (m, 1H). APCI-MS: m/z 198 [MH*] (iii) N-(2-{3-{3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy} 25 phenyl)-acetamide hydrochloride A solution of 3-(4-Chloro-phenoxy)-pyrrolidine (0.059 g, 0.298 mmol) and N-acetyl-2 (2,3-epoxypropoxy)aniline (0.062 g, 0.299 mmol) in EtOH (1.5 ml, 99.5%) was stirred for 3 hours at 75"C in a sealed vial. The solvent was evaporated after completion of the reaction and the residue was purified on silica (CH 2 Cl 2 :MeOH, 98:2 to 97:3) to give 88 mg 30 of the free amine of the title compound. The amine was dissolved in MeOH : water 1:1 WO 01/62728 PCT/SEO1/00403 48 (30 ml), and the solution was acidified with 2M hydrochloric acid. The methanol was evaporated and the residual water solution was lyophilized to give 92 mg (70%) of the title compound as a white solid. 5 APCI-MS: m/z 405.2, 407.2 [MH*, isotope pattern] Example 2 N-(5-Chloro-2-{3-{3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy} phenyl)-acetamide hydrochloride 10 (i) N-(5-Chloro-2-hydroxy-phenyl)-acetaniide A solution of 4-amino-2-chlorophenol (2.0g, 13.9 mmol) and acetic anhydride (1.77g, 17.3 mmol) in water (40 ml) was stirred vigorously for 5 minutes. The reaction mixture was then heated with stirring to 60*C for 30 minutes, and was then allowed to cool. A pink is solid was formed and the precipitate was collected by filtration, washed twice with water, and dried to give 1.8g (70%) of the subtitle compound. 'H-NMR (400 MHz, DMSO-d 6 ): 5 10.09 (1H, s); 9.25 (lH, bs); 7.93 (IH, s); 6.93 (1H, dd, J8.8, 2.7 Hz); 6.84 (1H, d, J8.6 Hz); 2.09 (3H, s) 20 APCI-MS: m/z 186.0 [MH*] (ii) N-(5-Chloro-2-oxiranylmethoxy-phenyl)-acetamide A solution of N-(5-Chloro-2-hydroxy-phenyl)-acetamide (0.499 g, 2.68 mmol), K 2 C0 3 (0.60 g, 4.35 mmol) and epibromohydrin (0.405 g, 2.95 mmol) in DMF (5 ml) was heated 25 with stirring at 50"C for 2 hours. The mixture was then partitioned between EtOAc and water 40+40 ml. The organic phase was washed twice with water and once with brine and finally concentrated in vacuo to give a crude product. The crude product was purified on silica (heptane: EtOAc, 1 : 1), to give 0.43 g (66%) of a white solid.
WO 01/62728 PCT/SEO1/00403 49 'H-NMR (400MHz, CDCl 3 ): 6 8.46 (1H, d, J2.3 Hz); 7.90 (1H, bs); 6.98 (1H, dd, J8.7, 2.4 Hz); 6.83 (1H, d,J8.8 Hz); 4.36 (1H, dd, J 11.5, 2.4 Hz); 3.94 (1H, dd, J 11.6, 6.0 Hz); 3.41-3.36 (1H, m); 2.97 (1H, dd, J4.7, 4.2 Hz); 2.80 (1H, dd, J4.6, 2.6 Hz); 2.23 (3H, s) 5 (iii) N-(5-Chloro-2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy propoxy}-phenyl)-acetamide hydrochloride Prepared by a process analogous to that described in Example 1, step (iii). Example 3 1o N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl) acetamide Prepared according to the methods described in Example 1. Purified and isolated as the free amine in 73% yield by C1 8 -column chromatography (H 2 0:CH 3 CN, 0. IM NH 4 0Ac 15 buffer, gradient 30% to 95% CH 3 CN). APCI-MS m/z: 453, 455 [MH*] 'H NMR (400 MHz, CDC1 3 ) : 7.32(d, 1H), 7.01(d, 1H), 6.85-8.80(m, 2H), 6.78-6.69 (m, 3H), 4.31 (m, 1H), 4.15-4.09(m, 1H), 4.18-3.18(bs, 3H), 2.91(m, 1H), 2.71(m, 1H), 20 2.62-2.52(m, 3H), 2.35(m, 1H), 2.05-1.93(m, 2H), 1.89-1.77(m, 2H) Example 4 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidiunyl]-2-propanol dihydrochloride 25 N-(2-f{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide (1.418g, 3.13 mmol) was dissolved in 50ml HC1 (35%/aq, puriss) and refluxed overnight. The product precipitated and was filtered and dried to give 0.835 g (65%) of the title compound. 30 WO 01/62728 PCT/SEO1/00403 50 APCI-MS m/z: 411, 413 [MH'] 'H NMR (400 MHz, CDC1 3 ) :8 8.39-3.31 (m, 2H), 7.31(d, 1H), 7.01-6.98(m, 3H), 6.94-6.91(m, 1H), 6.75(dd, 1H), 4.3 1(m, 1H), 4.12-4.02 (m, 2H), 3.92(dd, 1H), 2.90(m, 111), 2.69(m, 1H), 2.62-2.51(m, 2H), 2.46(dd, 1H), 2.34(m, 1H), 2.18(s, 3H), 5 2.04-1.93(m, 2H), 1.89-1.77(m, 2H). Example 5 N-(2-{3-[3-(3,4-dichlorophenoxy)-1-pyrrolidinyl)-2-hydroxypropoxy}phenyl) acetamide hydrochloride 10 Prepared according to the methods described in Example 1 to give 68mg (68%) of the title compound as a white solid. APCI-MS m/z: 439, 441 [MH*] is Example 6 2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoic acid methyl ester 20 (i) 2-Oxiranylmethoxy-benzoic acid methyl ester Prepared according to the method described in Example 2, step (ii). 'H-NMR: (400 MHz, CDC1 3 ): 8 7.81 (1H, dd, J7.7, 1.7Hz); 7.46 (1H, dt, J7.7, 1.7 Hz); 7.05-6.98 (2H, m); 4.33 (111, dd, J 11.3 , 3.0 Hz); 4.11 (1H, dd, J 11.3 , 4.8 Hz); 3.90 25 (3H, s); 3.43-3.37 (111, m); 2.93-2.90 (211, m) (ii) 2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoic acid methyl ester Prepared according to the method described in Example 1, step (ii). Isolated as the free 30 amine WO 01/62728 PCT/SEO1/00403 51 'H-NMR: (400 MHz, CDC1 3 ): 5 7.81 (1H, dd, J8.1 , 1.8 Hz); 7.46 (1H, dt, J7.8, 1.7 Hz); 7.03-6.91 (4H, m); 6.86-6.82 (2H, m); 4.28-4.10 (3H, m); 4.08-4.00 (1H, m); 3.88 (3H, s); 2.92-2-84 (1H, m); 2.83-2.76 (1H, m); 2.66-2.53 (2H, m); 2.46 (1H, t, J 10.2 Hz); 2.36 5 (1H, t, J10.2 Hz); 2.02-1.92 (2H, m); 1.86-1.74 (2H, m); 1.63 (1H, bs) APCI-MS: m/z 404.2 [MH*] Example 7 2-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} 10 benzoylamino)-2-methyl-propionic acid methyl ester (i) Methyl 2-[(2-hydroxybenzoyl)amino] -2-methylpropanoate To a solution of 2-(chlorocarbonyl)phenyl acetate (20 mmol, 3.96g) in toluene (50ml) were N-ethyl-N,N-diisopropylamine (22 mmol, 2.84g) and 2-methylalanine (22 mmol, 2.27g) is added. After stirring the reaction mixture at room temperature overnight, the mixture was diluted with 250ml toluene and was washed with 1.8% HCl/aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na 2
SO
4 and concentrated under reduced pressure. The residue was dissolved in MeOH (50mL) and 3 drops of conc. H 2 S0 4 were added. The mixture was refluxed for 2 hours and concentrated under reduced pressure. 20 The residue was dissolved in 250mL EtOAc and washed with sat.NaHCO 3 /aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na 2
SO
4 and concentrated at reduced pressure. The resulting crude material was used without further purification. APCI-MS m/z: 238 [MH+] 25 (ii) Methyl 2-methyl-2-{[2-(2-oxiranylmethoxy)benzoyl amino}propanoate A solution of methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate, K 2 C0 3 (20 mmol, 2.68g) and 2-(chloromethyl)oxirane (22 mmol, 2.03g) in acetonitrile (60 ml) was stirred at reflux temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1.8% HC1/aq (250 ml) and sat. NaC1/aq (250 ml). The organic phase was dried over 30 Na 2
SO
4 and concentrated at reduced pressure. The residue was purified on Ci 8 -column WO 01/62728 PCT/SEO1/00403 52
(H
2 0:CH 3 CN, 0. IM NH 4 0Ac buffer, gradient 10% to 95% CH 3 CN) to give the subtitle compound (244mg, 5% yield, two steps). APCI-MS m/z: 294 [MH+] 5 'H NMR (400 MHz, CDCl 3 ) :6 8.40(s, 1H), 8.14 (dd, 1H), 7,41 (dt, 1H), 7.07 (t, 1H), 6.90 (d, 1H), 4,44 (dd, 1H), 4.07 (dd, 1H), 3.74 (s, 3H) , 3.45 (m, 1H) , 2.94 (dd, 1H), 2.84 (dd, 1H), 1.64 (d, 6H) (iii) 2-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} 10 benzoylamino)-2-methyl-propionic acid methyl ester A toluene solution of 4-(3,4-difluorophenoxy)piperidine (0.03 ml, 0.5 M) was mixed with a toluene solution of methyl 2-methyl-2- {[2-(2-oxiranylmethoxy)benzoyl]amino } propanoate (0.03 ml, 0.5 M). The mixture was diluted with 0.20 ml toluene and 0.05 ml methanol. The reaction mixture was stirred- overnight at 100" C in sealed vials. The 15 product were concentrated in vacuo and used without any purification. APCI-MS m/z: 507 [MH+] 'H NMR (400 MHz, CDCl 3 ) :8 8.13(s, 1H), 7.90 (dd, 1H), 7.33 (dt, 1H), 7.07-6.96 20 (m, 2H), 6.89 (d, 1H), 6.73-6.68 (m, 1H), 6.58-6.55 (m, 1H), 4.77-4.72 (m, 1H), 4.49 (bs, 1H), 4.20-4.13 (m, 2H), 3.69 (s, 3H), 3.58-3.44 (m, 2H), 3.39-3.26 (m, 4H), 2.54-2.40 (m, 2H), 2.13-2.04 (m, 2H), 1.60 (d, 6H) Example 8 25 N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2 hydroxycyclopentyl}oxy)phenyllacetamide and N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2 hydroxycyclopentyl}oxy)phenyl]acetamide 30 (i) N-[2-(2-cyclopenten-1-yloxy)phenyllacetamide WO 01/62728 PCT/SEO1/00403 53 To a suspension of sodium hydride (60 proc. in paraffin; 297 mg, 7.43 mmol, 1.1 equiv.) in DMF (3 ml) a solution of 2-acetamido-phenol (1.02 g, 6.75 mnol, 1.0 equiv.) in DMF (12 ml) was added dropwise at 0 0 C. After 30 minutes chlorocyclopent-2-ene (R. Moffett, Organic Synthesis, Wiley: New York 1963, Collect. Vol. IV, p.238-241) (762 mg, 5 0.76 ml, 7.43 mmol, 1.1 equiv.) was added by a syringe and stirring was continued overnight. Aqueous work-up followed by flash chromatography on silica gel (heptane/ethyl acetate, 2:1 continued to 1:1) afforded 992 ing (68 %) of the subtitle compound as a dark, yellow oil. 1o 'H-NMR (400 MHz, CDCl 3 ): 6 8.35 (lH, d, J 8.0Hz), 7.73 (lH, bs), 7.00 (1H, td, J 7.9, 1.5Hz), 6.90-6.95 (2H, m), 6.17 (lH, m), 5.95 (1H, m), 5.36 (lH, d, J 5.9Hz), 2.59 (1H, m), 2.38 (2H, m), 2.17 (3H, s), 1.97 (1H, m). MS-ESI+ : m/z 218.1 [MH+]. is (ii) N-{2-(6-oxabicyclo(3.1.0]hex-2-yloxy)phenyl}acetamide To an ice bath cooled solution of N-[2-(2-cyclopenten-1-yloxy)phenyl]acetanide (149 mg, 686 pmol, 1.0 equiv.) in dichloromethane (4 ml) m-chloroperbenzoic acid (85 proc.; 146 pLmol, 1.1 equiv.) was added. After stirring overnight with slowly warming up to an ambient temperature the reaction mixture was diluted by tertbutyl(methyl)ether, washed 20 successively by a sat. sodium bisulfate solution, 5 proc. sodium hydroxide and brine and dried over sodium sulfate. Evaporation of the solvent and flash chromatography on silica gel (ethyl acetate/heptane, 2:3 continued to ethyl acetate) yielded 93 mg (58 %) of the subtitle compound as a mixture of the trans, (minor) and the cis (major) diastereoisomeric epoxides as a pale yellow oil. The cis/trans ratio was determined as 2:1 by 'H-NMR. 25 'H-NMR (400 MHz, CDCl 3 ): 6 8.39 (lH [A], m), 8.34 (lH [B], d, J 8.2Hz), 7.91 (lH [A], bs), 7.59 (lH, [B], bs), 6.92-7.25 (3H [A] + 3H [B], m), 4.89 (lH [B], d, J 5.2Hz), 4.77 (lH [A], td, J 8.0, 1.3Hz), 3.66 (lH [B], m), 3.64 (1H [B], m), 3.60 (1H, [A], m), 3.54 (lH [A], m), 2.23 (1H [B], d, J 8.4Hz), 2.21 (3H [A], s), 2.19 (3H [B], s), 2.10 (2H [A], m), 30 1.72-1.92 (m), 1.53-1.63 (in) (2H [A]+ 3H [B]). (A=trans, B=cis) WO 01/62728 PCT/SEO1/00403 54 MS-ESI+: m/z 234.1 [MH+). (Mi) N-[2-({(1R,2S,3R)*-3~[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2 hydroxycyclopentyl}oxy)phenyl]acetamide and 5 N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2 hydroxycyclopentyl}oxy)phenyl)acetamide N- {2-(6-oxabicyclo[3. 1.0]hex-2-yloxy)phenyl} acetamide (racemic mixture of the trans and cis diastereoisomers) (87 mg, 373 imol, 1.0 equiv.) and 4-(3,4-dichlorophenoxy)piperidine (92 mg, 394 gmol, 1.06 equiv.) were dissolved in 2 M lithium perchlorate in acetonitrile 10 (3 ml) and heated in a sealed tube over night at 85 *C. Aqueous work-up and flash chromatography of the crude on silica gel (heptane/ethyl acetate/methanol/ammonia 1:3:0:0 continued to 0:90:10:1 to 0:80:20:3) led to the separation of two diastereoisomeric addition products to give 24 mg (14 %) of the (1 S,2S,3R) diastereoisomer (first eluted) and 75 mg (42 %) of the second eluted (lR,2S,3R) diastereoisomer. 15 For (1S,2S,3R) diastereoisomer: 'H-NMR (400 MHz, CDC1 3 ): 6 8.27 (1H, dd, J 7.6, 1.7Hz), 7.91 (1H, s), 7.29 (1H, d, J 8.9Hz), 6.88-7.00 (4H, m), 6.73 (1H, dd, J 8.9, 2.8Hz), 4.45 (1H, m), 4.28 (1H, hept, J 3.6Hz), 4.18 (1H, dd, J 7.1, 4.6Hz), 2.87 (3H, in), 2.71 (1H, q, J 7.5Hz), 2.15 (3H, s), 2.11 20 (IH, m), 1.78-2.02 (7H, m). MS-APCI+: m/z 479.1 [MH+]. For (1R,2S,3R) diastereoisomer: 'H-NMR (400 MHz, CDCl 3 ): 8 8.20-8.25 (2H, m), 7.29 (1H, d, J 8.9Hz), 6.91-7.00 (4H, 25 m), 6,74 (1H, dd, J 8.9, 2.8Hz), 4.46 (1H, bq, J 4.8Hz), 4,29 (1H, m), 4.13 (1H, d, J 7.2Hz), 2.95 (2H, m), 2.84 (2H, m), 2.50 (2H, m), 2.15 (3H, s), 1.93-2.07 (5H, m), 1.82 (2H, m), 1.58 (1H, m). MS-APCI+: m/z 479.1 [MH+]. 30 Example 9 WO 01/62728 PCT/SEO1/00403 55 N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2 hydroxycyclohexyl}oxy)phenyl]acetamide (i) N-[2-(2-cyclohexen-1-yloxy)phenyllacetamide 5 2-Cyclohexenol (491 mg, 0.49 ml, 5.00 mmol, 1.0 equiv.), 2-acetamidophenol (756 mg, 5.00 mmol, 1.0 equiv.) and triphenylphosphine (1.44 g, 5.50 mmol, 1.1 equiv.) were dissolved in THF (10 ml) and kept at ambient temperature by a water bath. After dropwise addition of diethyl azodicarbonic acid (871 mg, 0.78 ml, 5.00 mmol, 1.0 equiv.), dissolved in THF (3 ml), the reaction mixture was stirred over night. Extractive work-up and flash 10 chromatography on silica gel (heptane/tertbutyl(methyl)ether = 1:1) afforded 224 mg (19 %) the title compound as a yellow oil. MS-ESI+: m/z 232.2 [MH+]. is (ii) N-[2-(7-oxabicyclo[4.1.0]hept-2-yloxy)phenyl]acetamide To a solution of N-[2-(2-cyclohexen-1-yloxy)phenyl]acetamide (76 mg, 329 pmol, 1.0 equiv.) in dichloromethane (5 ml) m-chlorobenzoic acid (85 proz.; 121 mg, 559 imol, 1.7 equiv.) was added at 0*C. Stirring was continued overnight while the reaction mixture was allowed to warm up slowly to room temperature. The heterogenous mixture was diluted 20 with ethyl acetate and washed with sat. sodium sulfite, 5 % sodium hydroxide and brine. Drying over sodium sulfate, evaporation of the solvent and flash chromatography on silica gel provided 59 mg (73 %) of the title compound as a mixture of the diastereoisomers (ratio A:B = trans:cis = 5:3 ['H-NMR]). 25 'H-NMR (400 MHz, CDCl 3 ): 6 8.35 (1H [A] + 1H [B], m), 8.02 (1H [A], bs), 7.70 (1H [B], bs), 6.95-7.04 (3H [A] + 3H [B], m), 4.62 (1H [A], dd, J-8.4, 5.5, 2.1Hz), 4.55 (1H [B], dd, J 7.5, 6.7Hz), 3.30-3.36 (2H [A] + 1H [B], m), 3.19 (1H [B], t, J 3.6Hz), 1.26-2.23 (10H [A] + 10H [B], m). 30 LC/MS-ESI+: m/z 248.1 [MH+ (A)], 248.2 [MH+ (B)].
WO 01/62728 PCT/SEO1/00403 56 (ill) N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2 hydroxycyclohexyl}oxy)phenyl]acetamide The diastereoisomeric mixture of N-[2-(7-oxabicyclo[4.1.0]hept-2-yloxy)phenyl]acetamide 5 (59 mg, 239 pmol, 1.0 equiv.) and 4-(3,4-dichlorophenoxy)piperidine (56 mg, 239 p.mol, 1.0 equiv.) were dissolved in 2 M lithium perchlorate in acetonitrile (2 ml) and heated in a sealed tube over night at 85 'C. Aqueous work-up and flash chromatography on silica gel (heptane/ethyl acetate/methanol= 50:100:3) gave 86 mg (75 %) as a yellow oil in a diastereoisomeric ratio of 69:31 = A:B ('H-NMR). No separation of the diastereoisomers [o. on reversed phase columns could be observed. The relative stereochemistry of the major and minor diastereoisomers, respectively, could not be assigned due to the complex spectrum of the mixture. 'H-NMR (400 MHz, CDC1 3 ): 6 9.48 (1H [A],'bs), 9.25 (1H [B], bs), 8.46 (1H [A] + 1H i5 [B], t, J 9.1Hz), 7.22-7.32 (2H [A] + 1H [B], m), 6.93-7.08 (4H [A] + 5H [B], m), 6.72-6.76 (1H [A] + 1H [B], m), 4.08-4.30 (3H [A] + 3H [B], m), 3.55-3.64 (2H [A] + 1H [B], m), 2.96-3.07 (2H [A] + 2H [B], m), 2.71 (2H [A] + 3H [B], m), 2.19 (3H [A], s), 2.16 (3H [B], s), 1.47-2.37 (10 H [A] + 1OH [B], m). MS-ESI+: m/z 493.1 [MH+ (A, B)]. 20 The following compounds were prepared by routes analogous to those described in the previous Examples. Example 10 25 N-(5-Chloro-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide APCI-MS: m/z 473.1 475.1 [MH*] 30 Example 11 WO 01/62728 PCT/SEOI/00403 57 N-(3-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy-5 methyl-phenyl)-acetamide APCI-MS: m/z 495.1 497.1 [MW'] 5 Example 12 N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yIJ-2-hydroxy-propoxy}-4-methyl phenyl)-acetaniide t0 APCI-MS: ni/z 453.1 455.1 [MH'] Example 13 N-(2-{3-13-(3,4-Dichloro-phenoxy)-pyrrolidin-1-ylJ-2-hydroxy-propoxy}-5-fluoro phenyl)-acetamide 15 -APCI-MS:- n/z 457.1 459.1 [MH+] Example 14 1- [3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl -3-(1H-indol-7-yloxy)-propan-2-ol 20 APCI-MS: m/z 421.1 423.1 [MH+] Example 15 1-(7-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-y] -2-hydroxy-propoxy}-indol-1-yl) 25 ethanone APCI-MS: ni/z 463.1 465.1 [MH+] Example 16 WO 01/62728 PCT/SEOI/00403 58 N-(4-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-ylJ-2-hydroxy-propoxy}-biphenyl-3 yl)-acetamide APCI-MS: m/z 515.1 517.1 [MH+] 5 Example 17 N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro phenyl)-acetamide 10 APCI-MS: ni/z 457.1 459.1 [MH 4 ] Example 18 N-(2-{3- [3-(3 ,4-Dichloro-phenoxy)-pyrrolidin-1-yIJ-2-hydroxy-propoxy}-5-methyl phenyl)-acetamide APCI-MS: m/z 453.1 455.1 [MH+] Example 19 N-(2-{3-[3-(3,4-Dichloro-pheuoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS: m/z 439.1 441.1 [MH+] Example 20 25 N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide APCI-MS: mlz 43 9.1 44 1.1 [MHt] 30 Example 21 WO 01/62728 PCT/SEO1/00403 59 N-(3-Acetyl-2-{3- [3-(4-chloro-phenoxy)-pyrroidin-1-y] -2-hydroxy-propoxy}-5 methyl-phenyl)-acetamide APCI-MS: ntlz 46 1.1 [MH'] 5 Example 22 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-ylJ-2-hydroxy-propoxy}-4-methyl phenyl)-acetamide 10 APCI-MS: m/z 419.1 [MH'] Example 23 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-popoxy}-5-fluoro phenyl)-acetamide 15 APCI-MS: m/z 423.1 [iMH~] Example 24 1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-o 20 APCI-MS: rnlz 387.1 [MIH+] Example 25 1-(7-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-ylI-2-hydroxy-propoxy}-indol-1-yl) 25 ethanone APCI-MS: in/z 429.1 [MH+h1 Example 26 WO 01/62728 PCT/SEOI/00403 60 N-(4-{3-[3-(47Chloro-phenoxy)-pyrroidin-1-yl -2-hydroxy-propoxy}-bipheny-3-yl) acetamide APCI-MS: m/z 48 1.1 [MW'] 5 Example 27 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro phenyl)-acetamide 10 APCI-MS: m/z 423.1 [MH 4 ] Example 28 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-ylJ-2-hydroxy-propoxy}-5-methyl phenyl)-acetamide 15 APCJ-MS: m/z 419.1 [MHII Example 29 N.-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-ylJ-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS: m/z 405.1 [MH-'] Example 30 25 N-(5-Chloro-2-{3- [3-(4-fluoro-phenoxy)-pyrrolidin-1-yl] -2-hydroxy-propoxy} phenyl)-acetamide APCI-MS: m/z 423.1[M ] 30 Example 31 WO 01/62728 PCT/SEOI/00403 61 N-(3-Acetyl-2-{3-f3-(4-fluoro-phenoxy)-pyrroldin-1-y] -2-hydroxy-propoxy}1-5 methyl-phenyl)-acetamide APCI-MS: m/z 445.3 [MHii .5 Example 32 N-(2-{3- [3-(4-Fluoro-phenoxy)-pyrrolidin-1-yII-2-hydroxy-propoxy}-4-methyl phenyl)-acetamide 10 APCI-MS: m/z 403.3 [MH'] Example 33 N-(5-Fluoro-2-{3- [3-(4-fluoro-phenoxy)-pyrrolidin-1-yl] -2-hydroxy-propoxy}-phenyl) acetamide 15 APCI-MS: m/z 407.1 [MH'] Example 34 1-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yI]-3-(1H-indol-7-yloxy)-propan-2-ol 20 APCI-MS: m/z 371.1 [MH'] Example 35 1-(7-{3-13-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-y) 25 ethanone APCI-MS: m/z 413.1 [MH'] Example 36 WO 01/62728 PCT/SEOI/00403 62 N-(4-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl] -2-hydroxy-propoxy}-biphenyl-3-yl) acetamide APCI-MS: m/z 465.3 [MH'] 5 Example 37 N-(4-Fluoro-2-{3-[3-(4-fluoro--phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) acetainide 10 APCI-MS: mlz 407.1 [MH'] Example 38 N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrroldin-1 -yiI -2-hydroxy-propoxy}-5-methyl phenyl)-acetamide 15 APCJ-MS: mlz 403.1 [MH'I Example 39 N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS: m/z 389.1 [MH~] Example 40 25 N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy} phenyl)-acetamide APCI-MS: m/z 441.1 [MH+] 30 Example 41 WO 01/62728 PCT/SEO1/00403 63
N-(
3 -Acetyl-2-{3-[3-(3,4-difluoro-phenoxy)-pyrroUdin-1-yl]-2-hydroxy-propoxy}-5 methyl-phenyl)-acetamide APCI-MS: m/z 463.3 [MH~] 5 Example 42 N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl phenyl)-acetamide 1o APCI-MS: m/z 421.1 (MH~] Example 43
N-(
2
-{
3 -[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl-2-hydroxy-propoxy}-5-fluoro phenyl)-acetamide 15 APCI-MS: m/z 425.1 [MW] Example 44 1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol 20 APCI-MS: m/z 389.1 [MW] Example 45 1-(7-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-indol-1-yl) 25 ethanone APCI-MS: m/z 431.1 [MH~] Example 46 WO 01/62728 PCT/SEOI/00403 64 N-(4-{3-[3-(3,4-Difluoro-phenoxy)-.pyrrolidin-1-y] -2.-hydroxy-propoxy} -biphenyl-3 yl)-acetamide APCI-MS: m/z 483.3 [MH{] 5 Example 47 N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolldin-1-ylJ-2-hydroxy-propoxy -4-fluoro phenyl)-acetamide 10 APCI-MS: m/z 425.1 [ vllfl Example 48 N-.(2-{3-[3-(3,4-Difluoro-pbenoxy)-pyrrolldin-1 -yI]-2-hydroxy-propoxy}-5-methyl phenyl)-acetamide APCI-MS: rn/z 42 1.1 [MIHf'] Example 49 N-(2-{3-13-(3,4-Difluoro-pheoxy)-pyrrolidin-1-ylI-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS: rn/z 407.1 [MWi] Example 50 25 N-(5-Chloro-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-ylJ-2-hydroxy-propoxy} phenyl)-acetamide APCI-MS: m/z 487.1 489.1 [MW-] 30 Example 51 WO 01/62728 PCT/SEOI/00403 65 N-(3-Aceiyl-2-{3-[4-(34-dichloro-phenoxy)-piperidin-1-yl] -2-hydroxy-propoxy}-5 methyl-phenyl)-acetamide APCI-MS: ni/z -509.1 511.1 [MW-] 5 Example 52 N-(2-{3-14-(3,4-Dichloro-phenoxy)-piperidin-1-yl -2-hydroxy-propoxy}-4-methyl phenyl)-acetainide 10 APCI-MS: m/z 467.1 469.1 [MH~] Example 53 N-(2-{3- [4-(3,4-Dichloro-phenoxy)-piperidin-1-yll-2-hydroxy-propoxy}-5-fluoiro phenyl)-acetamide 15 APCI-MS: m/z 471.1 473.1 [MW] Comparison Example 54 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol 20 APCI-MS: m/z 435.1 437.1 [MHW] Example 55 1-(7-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl] -2-hydroxy-propoxy}-indol-1-yl) 25 ethanone APCI-MS: m/z 477.1 479.1 [MITE] Example 56 WO 01/62728 PCT/SEOI/00403 66 N-(4-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl] -2-hydroxy-propoxy}-biphenyl-3 yl)-acetamide APCI-MS: mlz 429.1 43 1.1 [MWH] 5 Example 57 N-(2-{3-[4-(3,4-Dichloro-plienoxy)-piperidin-1-yl -2-hydroxy-propoxy)-4-fluoro phenyl)-acetamide 10 APCI-MS: m/z 471.1 473.1 Mi Example 58 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl -2-hydroxy-propoxy}-5-methyl phenyl)-acetaniide 15 APCI-MS: m/z 467.1 469.1 [MW-] Example 59 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-ylI-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS: mlz 453.1 455.1 [MH-] Example 60 25 N-(5-Chloro-2-{3-[4-(4-chloro-phenoxy)-piperidin-1-yIJ-2-hydroxy-propoxy}-phenyl) acetamide APCI-MS: m/z 453.1 455.1 [MH-] 30 Example 61 WO 01/62728 PCT/SEOI/00403 67 N-(3-Acetyl-2-3-[4-(4-choro-phenoxy)-piperidin-1-ylI-2-hydroxy-propoxy}-5-methyl phenyl)-acetamide APCI-MS: m/z 475.3 [MH'] 5 Example 62 N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yII-2-hydroxy-propoxy}-4-methyl-pheny) acetamide 10 APCI-MS: m/z 433.1 [MH'] Example 63 N-(2-{3-[4-;(4-Chloro-phenoxy)-piperidin-1-yl] -2-hydroxy-propoxy}-5-fluoro-phenyl) acetainide 15 APCI-MS: m/z 437.1 [MH'] Comparison Example 64 1-[4-(4-Chloro-phenoxy)-piperidin-1-ylJ-3-(1H-indol-7-yloxy)-propan-2-ol 20 APCI-MS: mlz 401.1 [MiH'] Example 65 1-(7-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-indol-1-yl) 25 ethanone APCI-MS: m/z 443.1 [MH] Example 66 WO 01/62728 PCT/SEO1/00403 68 N-(4-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} -biphenyl-3-yl) acetamide APCI-MS: m/z 495.3 [MH*] 5 Example 67 N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl) acetamide 10 APCI-MS: m/z 437.1 [MH*] Example 68 N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl) acetamide 15 APCI-MS: m/z 433.1 [MH*] Example 69 N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS: m/z 419.1 [MH*] Example 70 25 N-{5-Chloro-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-blindol-2-yl)-2-hydroxy propoxyl-phenyl}-acetamide APCI-MS: m/z 448.1 450.1 [MHW] 30 Example 71 WO 01/62728 PCT/SEOI/00403 69 N-{3-Acetyl-2-[3-(8-chloro-1 ,3,4,5-tetrahydro-pyrido [4,3-b] indol-2-yl)-2-hydroxy propoxy]-5-methyl-phenyl}-acetamide APCI-MS: m/z 470.1 [MH'] 5 Example 72 N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido (4,3-b] indol-2-yI)-2-hydroxy-propoxy] -4 methyl-phenyl}-acetaniide 10 APCI-MS: m/z 428.1 [NMW] Example 73 N-{2- [3-(8-Chloro-1,3,4,5-tetrahydro-pyrido (4,3-b] indol-2-yl)-2-hydroxy-propoxyl-5 fluoro-phenyl}-acetamide 15 APCI-MS: m/z 432.1 [MW'] Example 74 1 -(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-blindol-2-y1)-3-(1H-iindol-7-yloxy)-propan 20 2-ol APCI-MS: m/z 396.1 [MH-] Example 75 25 1-{7-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido (4,3-b] indol-2-y1J-2-hydroxy-propoxyl indol-1-yl}-ethanone APCI-MS: n]/z 438.1 [MW-] 30 Example 76 WO 01/62728 PCT/SEOI/00403 70 N-{4-13-(8-Chloro-1 ,3,4,5-tetrahydro-pyrido 14,3-blindol-2-yl)-2-hydroxy-propoxyl biphenyl-3-yl}-acetainide APCI-MS: m/z 490.1 [MW-] 5 Example 77 N-{2- [3-(8-Chloro-1,3,4,5-tetrahydro-pyrido [4,3-blindol-2-yl)-2-hydroxy-propoxyJ-4 fluoro-phenyl}-acetamide 10 APCI-MS: nilz 432.1 [MW-] Example 78 N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido f4,3-blindol-2-yl)-2-hydroxy-propoxyj-5 methyl-phenyl}-acetainide 15 APCI-MS: m/z 428.1 [MW ] Example 79 N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido [4,3-blindol-2-yl)-2-hydroxy-propoxy 20 phenyl}-acetamide APCI-MS: m/z 414.1 [Nll-I] Example 80 25 N-{5-Chloro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido [4,3-b]indol-2-yl)-2-hydroxy propoxyl-phenyl}-acetamide APCI-MS: m/z 432.1 [MH'] 30 Example 81 WO 01/62728 PCT/SEOI/00403 71 N-{3-Acetyl-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[f4,3-b] indol-2-yI)-2-hydroxy propoxy]-5-methyl-phenyl}-acetamide APCI-MS: m/z 454.3 [MH-] 5 Example 82 N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido t4,3-blindol-2-yl)-2-hydroxy-propoxyl-4 methyl-phenyl}-acetamide 10 APCI-MS: m/z 412.1 [MW-] Example 83 N-{5-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido 14,3-bi indol-2-yl)-2-hydroxy propoxy] -phenyl}-acetaniide 15 APCI-MS: mlz 416.1 [W Example 84 1-(8-Fluoro-1,3,4,5-tetrahydro-pyrido [4,3-b] indol-2-yl)-3-(1H-indol-7-yloxy)-propan 20 2-ol APCJ-MS: m/z 380.1 [MIHf] Example 85 25 1-{7-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido(4,3-blindol-2-yl)-2-hydroxy-propoxyl indol-1-yl}-ethanone APCI-MS: mn/z 422.1 [MWH] 30 Example 86 WO 01/62728 PCT/SEOI/00403 72 N-{4-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido [4,3-blindol-2-yl)-2-hydroxy-propoxy biphenyl-3-yl}-acetamide APCI-MS: mlz 474.3 [MH-] 5 Example 87 N-{4-Fluoro-2- [3-(8-fluoro-1,3,4,5-tetrahydro-pyrido f4,3-blindol-2-yl)-2-hydroxy propoxy] -phenyl}-acetamide 10 APCI-MS: in/z 416.1 [MIH' Example 88 N-{2-13-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-blindol-2-yl)-2-hydroxy-propoxy-5 methyl-phenyl}-acetainide 15 APCI-MS: mlz 412.1 [MH'] Example 89 N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-blindol-2-yl)-2-hydroxy-propoxyl 20 phenyl}-acetamide APCI-MS: m/z 398.1 [MIH'] Example 90 25 N-(2-{3-14-(3,4-Dichloro-phenoxy)-piperidiu-1-ylI-2-hydroxy-propoxy}-phenyl) acetamide APCI-MS mlz: 453, 455 [MH±] 30 Example 91 WO 01/62728 PCT/SEOI/00403 73 3-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-y] -2-hydroxy-propoxy}-phenyl) propionic acid methyl ester APCI-MS m/z: 482, 484 [MH+] 5 Example 92 1- [4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-o NPCI-MS mlz: 456, 458 [MH+] 10 Example 93 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-y1I-3-(2-methoxy-phenoxy)-propan-2-oI NPCI-MS mlz: 426, 428 [MH+] 15 Example 94 2-{3- [4-(3,4-Dichloro-phenoxy)-piperidin-1-yI]-2-hydroxy-propoxy-N,N-dimethyl benzamide 20 APCI-MS mlz: 467, 469 [MH+] Example 95 1-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl] -2-hydroxy-propoxy}-phenyl) propan-1-one 25 APCI-MS mlz: 452, 454[TM+] Example 96 1-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yll-2-hydroxy-propoxy}-phenyl) 30 ethanone WO 01/62728 PCT/SEO1/00403 74 APCI-MS m/z: 438, 440 [MH+] Example 97 5 3-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester APCI-MS m/z: 418 [MH+] 10 Example 98 1-(2,6-Dimethoxy-phenoxy)-3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-propan-2-oI APCI-MS m/z: 392 [MH+] 15 Example 99 1-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol APCI-MS m/z: 362 [MH+] 20 Example 100 (2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester APCI-MS m/z: 447 [MH+] 25 Example 101 (2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy} benzoylanino)-acetic acid methyl ester 30 APCI-MS m/z: 491 [MH+] WO 01/62728 PCT/SEOI/00403 75 Example 102 2-(2-{3-13-(4-Fluoro-phenoxy)-pyrrolidin-1-ylI -2-hydroxy-propoxy}-benzoylamino)-2 methyl-propionic acid methyl ester 5 APCI-MS m/z: 475 [MIH+] Example 103 2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-propoxy}-N,N-dimnethyl 10 beuzamide APCI-MS m/z: 403 [MIH+] Example 104 15 1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone APCI-MS m/z: 404 [MH+] 20 Example 105 1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl -2-hydroxy-propoxy}-phenyl)-propan 1-one APCI-MS m/z: 388 [MH+] 25 Example 106 1..(2-{3-13-(4-Fluoro-phenoxy)-pyrrolidin-1-yl-2-hydroxy-propoxy}-phenyl)-ethanone APCJ-MS mlz:374 [MH+] 30 WO 01/62728 PCT/SEO1/00403 76 Example 107 N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4 methylphenyllacetamide 5 APCI-MS: m/z 480[MW] Example 108 3-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester 10 APCI-MS m/z: 436 [MH+] Example 109 1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol 15 APCI-MS m/z: 380 [MH+] Example 110 (2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) 20 acetic acid methyl ester APCI-MS m/z: 465 [MH+] Example 111 25 2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide APCI-MS m/z: 421 [MH+] 30 Example 112 WO 01/62728 PCT/SEOI/00403 77 1 -(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1 -ylJ-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanoue APCI-MS m/z: 422 [MIH+] Example 113 1-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-ylI-2-hydroxy-propoxy}-phenyl) propan-1-one 10 APCI-.MS m/z: 406 [MI-1±+] Example 114 1 -(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrroidin-1-yl]-2-hydroxy-propoxy}-phenyl) ethanone 15 APCI-MS m/z: 392 WM+] Example 115 N-(2-{3-[4-(3,4-dichloroanilino)--piperidinylj-2-hydroxypropoxyjphenyl)acetamide 20 APCI-MS: m/z 452.1 [\fl{] Example 116 3-(2-3-[3-4-Chloro-phenoxy)-pyrroidiu-1-yIJ-2-hydroxy-propoxy}-phenyl) 25 propionic acid methyl ester APCI-MS mlz: 434 [Ivll+] Example 117 30 1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-ylJ-3-(2,6-dimethoxy-phenoxy)-propan-2-oI WO 01/62728 PCT/SEO1/00403 78 APCI-MS m/z: 408 [MH+] Example 118 5 1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol APCI-MS m/z: 378 [MH+] Example 119 10 (2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid, methyl ester APCI-MS m/z: 463 [MH+] 15 Example 120 2-(2-{3-{3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2 methyl-propionic acid methyl ester APCI-MS m/z: 491 [MH+] 20 Example 121 2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide 25 APCI-MS m/z: 419 [MH+] Example 122 1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone 30 WO 01/62728 PCT/SEO1/00403 79 APCI-MS m/z: 420 [MH+] Example 123 1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan 5 1-one APCI-MS m/z: 404 [MH+] Example 124 10 1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone APCI-MS m/z: 390 [MH+] Example 125 15 N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) acetamide APCI-MS m/z: 396 [MH+] 20 Example 126 3-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic acid methyl ester APCI-MS m/z: 425 [MH+] 25 Example 127 (2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester 30 APCI-MS m/z: 454 [MH+] WO 01/62728 PCT/SEOI/00403 80 Example 128 2-{34[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl beuzamide 5 APCI-MS mlz: 410 [MH+] Example 129 4-f 1-12-Hydroxy-3-(2-propionyl-phenoxy)-propyl] -pyrrolidin-3-yloxy}-benzonitrile 10 APCI-MS m/z: 395 [MIH+j Example 130 N-(2-{2-Hydroxy-3-[3-(4-methoxy-phenoxy)-pyrrolidin-1-ylI-propoxy}-phenyl) 15 acetamide APCI-MS m/z: 401 [MH+] Example 131 20 N-(4-chloro-2-{3-I[4-(3,4-dichloroanilino)-1-piperidinyI]-2 hydroxypropoxy}phenyl)acetamide AIPCI-MS: mlz 486[MI1'] 25 Example 132 3-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolldiu-1-ylJ-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester APCI-MS mlz: 468, 470 [MII±] 30 WO 01/62728 PCT/SEO1/00403 81 Example 133 1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yll-3-(2-methoxy-phenoxy)-propan-2-o APCI-MS m/z: 412, 414 [MH+] 5 Example 134 (2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester 10 APCI-MS m/z: 497, 499 [MH+] Example 135 2-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester 15 APCI-MS m/z: 525, 527 [MH+] Example 136 2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl 20 benzamide APCI-MS m/z: 453, 455 [MH+] Example 137 25 1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone APCI-MS m/z: 454, 456 [MH+] 30 Example 138 WO 01/62728 PCT/SEO1/00403 82 1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) propan-1-one APCI-MS m/z: 438, 440 [MH+] 5 Example 139 1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) ethanone 10 APCI-MS m/z: 424, 426 [MH+] Example 140 N-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) acetamide 15 APCI-MS m/z: 421 [MH+] Example 141 3-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) 20 propionic acid methyl ester APCI-MS m/z: 450 [MH+] Example 142 25 2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide APCI-MS m/z: 435 [MH+] 30 Example 143 WO 01/62728 PCT/SEO1/00403 83 1-(2-{3-{4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propan-1-one APCI-MS m/z: 420 [MH+] 5 Example 144 (2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester 10 APCI-MS m/z: 479 [MH+] Example 145 N-(2-{3-[3-(3,4-Difluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}phenyl)-acetamide 15 APCI-MS m/z: 435 [MH+] Example 146 N-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS m/z: 403 [MH+] Example 147 25 3-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic acid methyl ester APCI-MS m/z: 432 [MH+] 30 Example 148 WO 01/62728 PCT/SEOI/00403 84 1-(2,6-Dimethoxy-phenoxy)-3-f4-(4-fluoro-phenoxy)-piperidin--yl -propan-2-ol APCI-MS inlz: 406 [MH+] 5 Example 149 1- [4-(4-Fluoro-phenoxy)-piperidin-1-ylI-3-(2-methoxy-phenoxy)-propan-2-ol APCI-MS mlz: 376 [MH+] 10 Example 150 1-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1 -yII-2-hydroxy-propoxy}-phenyl)-ethanone APCI-MS m/z: 388 [MH+] 15 Example 151 2.-{3- [4-(4-Fluoro-phenoxy)-piperidin-1-yl -2-hydroxy-propoxy}-N,N-dimethyl beuzamide APCI-MS m/z: 417 [MH+] 20 Example 152 1-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-y] -2-hydroxy-propoxy}-phenyl)-propan-1 one 25 APCI-MS mlz: 402 [MH+] Example 153 (2-{3-f4-(4-Fluoro-phenoxy)-piperidiu-1-ylI-2-hydroxy-propoxy}-benzoylamhlo) acetic acid methyl ester 30 WO 01/62728 PCT/SEOI/00403 85 APCI-MS m/z: 46,1 [MH+j Example 154 N-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yII-2-hydroxy-propoxy}-phenyl) 5 acetamide APCI-MS m/z: 417 [MH+] Example 155 10 3-(2-{3-3-(4-Fluoro-phenoxymethyl)-piperidin-1-ylI-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester APCI-MS m/z: 446 [MH+] 15 Example 156 1-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yll-3-(2-methoxy-phenoxy)- propan-2-oI APCI-MS m/z:390 [MH±] 20 Example 157 1-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl] -2-hydroxy-propoxy}-phenyl) ethanone APCI-MS inlz: 402 [MH+] 25 Example 158 2-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yll-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester 30 APCI-MS m/z: 503 [MH+] WO 01/62728 PCT/SEO1/00403 86 Example 159 2-{3- [3-(4-Fluoro-phenoxymethyl)-piperidin-1-yll-2-hydroxy-propoxy}-N,N-dimet hyl benzamide 5 APCI-MS mlz:43 1 [MH+] Example 160 1-(2-{3-[3-(4 -Fluoro-phenoxymethyl)-piperidin-1-yII-2-hydroxy-propoxy}-6-methoxy 10 phenyl)-ethanone APCJ-MS m/z: 432 [MH+] Example 161 15 N-(2-{3-[4-(4-Acetylamino-phenoxy)-piperidin-1-ylJ-2-hydroxy-propoxy}-phenyl) acetamide APCI-MS m/z: 442 [MH+] 20 Example 162 N-(4-{1-[3-(2-Acetyl-phenoxy)-2-hydroxy-propyl]-piperidi-4-yloxy}-phenyl) acetamide APCI-MS m/z: 427 [MH+] 25 Example 163 N-(4-cyano-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyll-2 hydroxypropoxylphenyl)acetamide 30 APCI-MS: m/z 477[MH'] WO 01/62728 PCT/SEO1/00403 87 Example 164 3-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic acid methyl ester 5 APCI-MS m/z: 448 [MH+] Example 165 1-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol 10 APCI-MS m/z: 392 [MH+] Example 166 1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone 15 APCI-MS m/z: 404 [MH+] Example 167 2-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2 20 methyl-propionic acid methyl ester APCI-MS m/z: 505 [MH+] Example 168 25 2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide APCI-MS m/z: 433 [MH+] 30 Example 169 WO 01/62728 PCT/SEO1/00403 88 1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone APCI-MS m/z: 434 [MH+] 5 Example 170 1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1 one 10 APCI-MS m/z: 418 [MH+] Example 171 (2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester 15 APCI-MS m/z: 477 [MH+] Example 172 N-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) 20 acetamide APCI-MS m/z: 433 [MH+] Example 173 25 3-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester APCI-MS m/z: 462 [MH+] 30 Example 174 WO 01/62728 PCT/SEO1/00403 89 1-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) ethanone APCI-MS m/z: 418 [MH+] 5 Example 175 2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide 10 APCI-MS m/z: 447 (MH+] Example 176 1-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propan-1-one 15 APCI-MS m/z: 432 [MH+] Example 177 N-[2-({(1R,2R)-2-[4-(3,4-dichlorophenoxy)-1-piperidinyll-1 20 hydroxycyclopentyl}methoxy)phenyllacetamide Example 178 Methyl (2S,4R)-1-{3-[2-(acetylamino)phenoxyl-2-hydroxypropyl}-4-[(4 chlorobenzyl)oxy]-2-pyrrolidinecarboxylate hydrochloride 25 Examples 179-189 Starting materials: A) (3,4-Dichloro-phenyl)-piperidin-4yl-amine WO 01/62728 PCT/SEO1/00403 90 In a nitrogen filled reaction vessel 4-oxo-piperidine- 1 -carboxylic acid tert-butyl ester (2.46g, 12.3 mmol) and 3,4-dichloro-phenylamine (1.0 g, 6.17 mmol) were dissolved in dichloromethane ( 28 ml) and acetic acid ( 2.12 ml). Sodium triacetoxyborohydride (3.67 g, 17.3 mmol) was added at room temperature. The reaction was stirred over night and then 5 poured into a sodium hydrogencarbonate solution (5%). The water phase was shaken three times with ethyl acetate (EtOAc). The combined organic phase was dried over sodium sulfate, evaporated and purified by flash chromatography (EtOAc : Heptane 3:7 ) giving 1.7 g, 81 % of pure compound. The BOC-protected title compound was dissolved in dichloromethane (26 ml) and trifluoro acetic acid (13 ml) and stirred at room temperature to for 3h, evaporated and dissolved in diethyl ether and sodium hydroxide (1 M). The organic layer was separated and the water phase washed twice with ether. The combined organic layer was washed with a small portion of brine, dried over sodium sulfate and evaporated to give 1.15g (76%) of the title compound. is 1 H-NMR (400MHz, DMSO-d6): 6 7.20 (d, 1H, J= 8.9 Hz), 6.73 (d, 1H, J = 2.7 Hz), 6.54 (dd, 1H, J= 8.8, 2.7 Hz), 5.95 (d, 1H, J = 8.1 .Hz), 3.22 (m, 1H), 2.91 (bd, 2H, J = 12.6 Hz), 2.51 (m, 2H), 2.02 (bs, 1H), 1.81 (bd, 2H, J= 12.4 Hz), 1.18 (m). APCI-MS: m/z 245 [M+] 20 B) (4-Chloro-phenyl)-piperidin-4yl-amine Was synthesised in the same way as (A) from 4-oxo-piperidine- 1 -carboxylic acid tert butyl ester (3.59 g, 18.0 mmol), 4-chloro-phenylamine (1.15 g, 9.0 mmol) and sodium triacetoxyborhydride (5.34 g, 25.2 mmol) in dichloromethane ( 40 ml) and acetic acid ( 3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 25 ml). Yield 1.5 g, 79 % 1H-NMR (400MHz, DMSO-d6): 8 7.04 (d, 2H, J = 8.9 Hz), 6.55 (d, 2H, J = 8.9 Hz), 5.62 (d, 1H, J = 8.1 Hz), 3.18 (m, 1H), 2.92 (bd, 2H, J = 12.6 Hz), 2.50 (m, 2H), 1.99 (bs, 1H), 1.82 (d, 2H, J = 12.7 Hz), 1.18 (m, 2H). 30 APCI-MS: m/z 211 [MH+] WO 01/62728 PCT/SEO1/00403 91 C) (4-Fluoro-phenyl)-piperidin-4yl-amine Was synthesised in the same way as (A) from 4-oxo-piperidine- 1 -carboxylic acid tert butyl ester (3.59 g, 18.0 mmol), 4-fluoro-phenylamine (1.0 g, 9.0 mmol) and sodium 5 triacetoxyborhydride (5.34 g, 25.2 mmol) in dichloromethane ( 40 ml) and acetic acid ( 3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.1 g, 63 % 1 H-NMR (400MHz, DMSO-d6): 8 6.85 (t, 2H, J = 9.0 Hz), 6.51 (dd, 2H, J = 9.1, 4.6 Hz), 10 5.27 (d, 1H, J= 8.2 Hz), 3.13 (m, 1H), 2.89 (bd, 2H, J= 12.5 Hz), 2.48 (m, 2H), 1.80 (bd, 2H, J = 12.3 Hz), 1.14 (m, 2H). APCI-MS: m/z 195 [MH+] D) (3,4-Difluoro-phenyl)-piperidin-4yl-amine 15 Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert butyl ester (3.59 g, 18.0 mmol), 3,4-difluoro-phenylamine (1.16 g, 9.0 mmol) and sodium triacetoxyborohydride (5.34 g, 25.2 mmol) in dichloromethane ( 40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.26 g, 66 % 20 1 H-NMR (400MHz, DMSO-d6): 6 7.05 (dt, 1H, J = 10.8, 9.2 Hz), 6.50 (ddd, 1H, J = 14.1, 7.0, 2.8 Hz), 6.32 (bd, 1H, J = 9.20 Hz), 5.64 (d, 1H, J = 8.14 Hz), 3.17 (m, 1H), 2.90 (bd, 2H, J = 12.6 Hz), 2.50 (m, 2H), 2.00 (bs, 1H), 1.81 (bd, 2H, J = 12.6 Hz), 1.16 (m, 2H) APCI-MS: m/z 213 [MH+] 25 Example 179 N-(2-{3-[4-(3,4-Dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4 methylphenyl)acetamide 30 APCI-MS: m/z 466[MH+] WO 01/62728 PCT/SEO1/00403 92 Example 180 N-(2-{3-4-(4-Chloroanilino)-1-piperidinyll-2-hydroxypropoxy} phenyl)acetamide 5 APCI-MS: m/z 418NM+] Example 181 N-(4-Chloro-2-{3- [4-(4-chloroanilino)-1-piperidinyl] -2-hydroxypropoxy~phenyl) acetamide 10 APCI-MS: m/z 452[MH+] Example 182 N-(2-{3-14-(4-Chloroauhlino)-l-piperidiuyll-2-hydroxypropoxy}-4 15 eyanophenyl)acetamide APCI-MS: m/z 443[MH+] Example 183 20 N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl] -2-hydroxypropoxy}-4 methylphenyl)acetamide APCI-MS: m/z 432WM+] 25 Example 184 N-(5-Chloro-2-{3-[4-(4-fluoroaniino)-1-piperidinyl]-2 hydroxypropoxy} phenyl)acetamide APCI-MS: m/z 436[MH-+] 30 WO 01/62728 PCT/SEO1/00403 93 Example 185 N-(5-Chloro-2-{3-[4-(3,4-difluoroanilino)-l-piperidinyl] -2 hydroxypropoxylphenyl)acetamide 5 APCI-MS: mn/z 454[MH+] Example 186 N-(5-Cyauo-2-{3- [4-(4-fluoroanilino)-1-piperidinylj-2-hydroxypropoxy} phenyl)acetamide 10 APCI-MS: m/z 427[MH+] Example 187 N-(5-Cyano-2-{3-14-(3,4-difluoroanilino)-1-piperidinyll-2 15 hydroxypropoxylphenyl)acetamide APCJ-MS: rn/z 445 [M-] Example 188 20 N-(2-{3-[4-(4-Fluoroanilino)-1 -piperidinyl] -2-hydroxypropoxy}-4 methylphenyl)acetamide APCI-MS: rn/z 416[MH+] 25 Example 189 N-(2-{3-[4-(3,4-Difluoroanilino)-1-piperidinyll-2-hydroxypropoxy}-4 methylphenyl)acetamide APCI-MS: m/z 434[MH+] 30 WO 01/62728 PCT/SEO1/00403 94 Example 190 N-(2-{3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy phenyl)acetamide 5 i) 3-(S)-(4-Chloro-phenoxy)-pyrrolidine CF 3 COOH To a solution of triphenyl phosphine (4.2 g, 16.02 mmol) in THF (75 mL) was added diethyl azodicarboxalate (2.52 mL) at 0 0 C, after 15 min 4-chlorophenol (2.05 g, 16.02 mmol) was added and after another 10 min 3-hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester (3.0 g, 16.02 mmol) in THF (20 mL) was added slowly. After addition was to complete the ice bath was removed and the reaction mixture was kept at room temperature overnight. The solvent was removed in vacuo and the residue was stirred with diethyl ether, the solid triphenyl phosphine was filtered off. The residue was purified by flash chromatography (0-0.5% MeOH in CHC1 3 ) to give the subtitled compound (3.65 g, 76%) which was dissolved in dichloromethane (60 mL) and trifluoroacetic acid (15 mL) was 15 added. The reaction mixture was kept at room temperature for 30 min. The solvent was removed in.vacuo. The residue was dissolved in dichloromethane, diethylether and hexane were added. The solid was filtered off to give the subtitled compound 3.70 g, 97%. 'H-NMR (CDCl 3 , 400 MHz): 6 10.20 (s, 1H), 9.99 (s, 1H), 7.25 (d, J 8.8 Hz, 2H), 6.78 (d, 20 J 8.8 Hz, 2H), 4.99 (m, 1H), 3.41 (m, 4H), 2.30 (m 1H), 2.20 (m, 1H). APCI-MS: m/z 198 (MH*). ii) N-(2-{3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy phenyl)acetamide 25 A mixture of 3-(S)-(4-chloro-phenoxy)-pyrrolidine.CF 3 COOH (312 mg, 1.0 mmol), N-acetyl-2-(2,3-epoxypropoxy)aniline (207 mg, 1.0 mmol), K 2 C0 3 (560 mg) in EtOH (10 mL) was stirred at 65 4C for 4 h. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous NHC1 solution, then with water. The organic layer was dried over Na 2
SO
4 , filtered, 30 concentrated. The residue was purified by flash chromatography (0-3% MeOH in CHCI 3
)
WO 01/62728 PCT/SEO1/00403 95 to give a mixture of diastereomers (310 mg, 77%). The diastereomers were seperated by HPLC to give N-(2- {3 -[3(S)-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy phenol)acetamide (57 mg) 5 'H-NMR (CDC1 3 , 400 MHz): 6 8.36 (m, 1H), 8.25 (s, 1H), 7.25 (m, 2H), 6.99 (m, 2H), 6.93 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.08 (m, 2H), 3.96 (m, iH), 3.11 (dd, J 5.9 10.5 Hz, 1H), 3.01 (m, 1H), 2.82 (m, 2H), 2.59 (m, iH), 2.51 (dd, J 3.2, 12.0 Hz, iH), 2.29 (m, 1H), 2.19 (s, 3H), 2.01 (m, 1H). APCI-MS: m/z 405 (MH*). 10 Example 191 N-(2-{3-{3S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2S-hydroxy-propoxy}-phenyl) acetamide hydrochloride The reaction was performed analogously to Example 190. 15 'H-NMR (CDC1 3 , 400 MHz): 5 8.35 (m iH), 8.26 (s, 1H), 7.24 (m, 2H), 6.99 (m, 2H), 6.92 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.12 (m, 2H), 3.95 (m, 1H), 2.95 (m, 2H), 2.80 (m, 3H), 2.52 (dd, 3.4, 12.2 Hz, iH), 2.30 (m, 1H), 2.19 (s, 3H), 2.01 (m, 1H). APCI-MS: m/z 405 (MH). 20 Example 192 N-(2-{3-{3(R)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(S)-hydroxy-propoxy phenyl)acetamide 25 The reaction was performed analogously to Example 190. 'H-NMR (CDC1 3 , 400 MHz): 5 8.36 (m, 1H), 8.25 (s, 1H), 7.25 (m, 2H), 6.99 (m, 2H), 6.93 (m, iH), 6.75 (m, 2H), 4.80 (m, 1H), 4.08 (m, 2H), 3.96 (m, 1H), 3.11 (dd, J 5.9 10.5 Hz, 1H), 3.01 (m, 1H), 2.82 (m, 2H), 2.59 (m, 1H), 2.51 (dd, J 3.2, 12.0 Hz, 1H), 2.29 (m, 30 IH), 2.19 (s, 3H), 2.01 (m, iH).
WO 01/62728 PCT/SEO1/00403 96 APCI-MS: m/z 405 (MH*). Example 193 N-[5-Chloro-2-({(2S)-3-[(3S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 5 hydroxypropyl} oxy)phenyl] acetamide The reaction was performed analogously to Example 190. 'H-NMR (CDC1 3 , 400 MHz): 5 8.45 (m, 1H), 8.36 (br. S, 1H), 7.23 (m, 2H), 6.95 (m, 1H), 10 6.85 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.07 (m, 2H), 3.91 (m, 1H), 2.95 (m, 2H), 2.80 (m, 3H), 2.49 (dd, J 3.2, 12.0 Hz, 1H), 2.30 (m, 1H), 2.19.(s, 3H), 2.03 (m, 1H). APCI-MS: m/z 439 (MH*). Example 194 15 N-[5-Chloro-2-({(2R)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl}oxy)phenyllacetamide The reaction was performed analogous to Example 190. 20 'H-NMR (CDCl 3 , 400 MHz): 5 8.45 (m, 1H), 8.36 (br. S, 1H), 7.23 (m, 2H), 6.95 (m, 1H), 6.85 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.07 (m, 2H), 3.91 (m, 1H), 2.95 (m, 2H), 2.80 (m, 3H), 2.49 (dd, J 3.2, 12.0 Hz, 1H), 2.30 (m, 1H), 2.19 (s, 3H), 2.03 (m, 1H). APCI-MS: m/z 439 (MH*). 25 Example 195 N-[5-Chloro-2-({(2S)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl}oxy)phenyllacetamide The reaction was performed analogously to Example 190. 30 WO 01/62728 PCT/SEO1/00403 97 'H-NMR (CDC 3 , 400 MHz): 6 8.45 (in, 1H), 8.34 (br. S, 1H), 7.22 (m, 2H), 6.94 (m, 1H), 6.85 (in, IH), 6.75 (in, 2H), 4.80 (m, 1H), 4.08 (n, 2H), 3.90 (m, 1H), 3.11 (dd, J 5.9, 10.5 Hz, 1H), 3.02 (in, 1H), 2.81 (in, 2H), 2.58 (in 1H), 2.49 (dd, J 3.5, 12.1 Hz, IH), 2.30 (i, 1H), 2.18 (s, 3H), 2.01 (in, 1H). 5 APCI-MS: m/z 439 (MH*). Example 196 N-[5-Chloro-2-({(2R)-3-[(3S)-3-(4-chloro-phenoxy)pyrrolidinyl-2 hydroxypropyl}oxy)phenyllacetamide 10 The reaction was performed analogous to Example 190. 'H-NMR (CDC1 3 , 400 MHz): 6 8.45 (m, 1H), 8.34 (br. S, 1H), 7.22 (in, 2H), 6.94 (m, 1H), 6.85 (m, 1H), 6.75 (in, 2H), 4.80 (m, 1H), 4.08 (m, 2H), 3.90 (m, 1H), 3.11 (dd, J 5.9, 10.5 is Hz, 1H), 3.02 (m, 1H), 2.81 (m, 2H), 2.58 (in 1H), 2.49 (dd, J 3.5, 12.1 Hz, 1H), 2.30 (m, 1H), 2.18 (s, 3H), 2.01 (in, 1H). APCI-MS: m/z 439 (MH*). Example 197 20 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4,5-difluoro phenyl)-acetamide i) 4,5-Difluoro-2-nitro-phenol In a flask was dissolved 3,4-Difluorophenol (3.10 g, 23.7 mmole) in acetic acid (15 ml). To 25 the stirred solution was added dropwise a solution of fuming HNO 3 (1.25 g, 29.7 mole) in acetic acid (6 ml). The temperature was kept under 50"C during the entire addition. After completed addition, the mixture was stirred for another hour. The reaction mixture was then poured onto ice-water, giving precipitation of a yellowish solid. The solid was collected by filtration, and dried. The solid was purified on silica (Heptane : EtOAc 5:1), WO 01/62728 PCT/SEO1/00403 98 giving the sub-title compound (2.05 g, 50%) as a yellow oil, which crystallizes on standing. 'H-NMR (400 MHz, CDC 3 ) 5: 10.61 (1H, s); 8.00 (1H, dd, J9.6 8.2 Hz); 7.00 (1H, dd, J 5 10.4 6.8Hz) ii) N-(4,5-Difluoro-2-hydroxy-phenyl)-acetamide In a flask was added the product obtained in i) (0.59 g, 3.37 mmole), and acetic acid (10 ml). The solution was heated with stirring to 90"C, and Tin (powder, 1.60 g, 13.5 mmole) 10 was added. The flask was sealed and heated with stirring for another hour, and the hot solution was filtered through celite. The filter was then washed with another 10 ml of hot acetic acid. To the filtrate was added water (25 ml) and acetic anhydride (0.5 ml, 5.29 mmole), and the resulting mixture was heated with stirring at 60*C for 20 minutes. The mixture was allowed to cool, and was partitioned between EtOAc and water. The organic 15 phase was collected and washed with water and brine. The organic phase was evaporated to give the 0.63 g (100%) of the sub-title compound as a solid. 'H-NMR (400 MHz, DMSO-d6) 6:10.25 (1H, s); 9.31 (lH, bs); 7.88 (lH, dd, J 12.8 7.9 Hz); 6.83 (1H, dd, J 12.1 7.7 Hz); 2.08 (3H, s) 20 iii) N-(4,5-Difluoro-2-oxiranylmethoxy-phenyl)-acetamide In a vial was added the compound obtained in ii) (0.4 g, 2.137 mmole), epibromohydrine (0.35 g, 2.55 mmole), K 2 C0 3 (0.6 g, 4.4 mmole) and DMF (2 ml). The vial was sealed and heated with stirring (2 hours, 60'C). The mixture was then partitioned between EtOAc and 25 water, and the organic phase was washed twice with water and once with brine, and was finally evaporated to give a brown solid. The crude epoxide was purified on silica, to give 0.27 g (52%) of the sub-title compound as a slightly pink solid.
WO 01/62728 PCT/SEO1/00403 99 'H-NMR (400 MHz, CDC1 3 ) 5: 8.37 (1H, dd, J 12.2 8.8 Hz); 7.85 (1H, bs); 6.78 (1H, dd, J 11.2 7.1 Hz); 4.34 (1H, dd, 11.5 2.2 Hz); 3.90 (1H, dd, 11.6 6.3 Hz); 3.40-3.36 (1H, m); 2.98 (1H t, J4.5 Hz); 2.81 (1H, dd, J4.7 6.3 Hz); 2.22 (3H, s) 5 iv) N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4,5-difluoro phenyl)-acetamide In a vial was added the compound obtained in iii) (0.059 g, 0.24 mmole), 3-(4 chlorophenoxy)-pyrrolidine (0.048 g, 0.24 mmole) and ethanol (2 ml, 99.5%). The vial was sealed and the content was heated with stirring to 75'C for 2 hours. The crude solution was io evaporated and the obtained oil purified on silica to the title compound which was lyophilized as the hydrochloride. The title compound was obtained as a white solid (0.075 g, 65%). The compound was a mixture of four stereoisomers, which had an effect on the NMR-spectra. is 'H-NMR (400 MHz, DMSO-d6) 6: 10.78-10.30 (1H, m); 9.30 (1H, s); 8.07 (1H, dd, J 12.8 9.3 Hz); 7.40-7.34 (2H, m); 7.23 (1H, dd, J 12.7 7.5 Hz); 7.05-6.99 (2H, m); 6.19 (1H, bs); 5.23-5.11 (lH, m); 4.35 (1H, bs); 4.08-3.97 (1.5H, m), 3.96-3.90 (1H, m); 3.84-3.70 (1.5H, m); 3.63-3.23 (4H, m); 2.66-2.00 (5H, m) 20 APCI-MS: m/z 411.1 [MH+] Example 198 N-{5-Chloro-2-[2-hydroxy-3-(3-phenoxy-pyrrolidin-1-yl)-propoxy-phenyl}-acetamide 25 The compound was prepared analogously to Example 197. 'H-NMR (400 MHz, DMSO-d6) 6:10.80-10.36 (1H, m); 9.26 (1H, s); 8.14 (lH, s); 7.32 (2H, t, J8.35 Hz); 7.11-6.95 (5H, m); 6.31-6.02 (1H, m); 5.24-5.12 (1H, m); 4.37 (1H, bs); 4.10-3.97 (1.5H, m); 3.95-3.88 (1H, m) 3.84-3.68 (1.5H, in); 3.64-3.26 (4H, m); 2.65-2.52 30 (0.5H, m); 2.35-2.02 (4.5H, m) WO 01/62728 PCT/SEO1/00403 100 APCI-MS: m/z 405.2 [MH+] Example 199 5 N-(5-Chloro-2-{2-hydroxy-3-[3-(4-nitro-phenoxy)-pyrrolidin-1-y]-propoxy}-phenyl) acetamide The compound was prepared analogously to Example 197. 10 'H-NMR (400 MHz, DMSO-d6) 5:10.95-10.48 (1H, m); 9.26 (1H, s); 8.24 (2H, d, J9.6 Hz); 8.13 (1H, bs); 7.23-7.17 (2H, m); 7.12-7.02 (2H, m); 6.20 (1H, bs); 5.43-5.30 (lH, m); 4.38 (IH, m); 4.18-4.06 (0.5H, m); 4.05-3.97 (1H, m); 3.95-3.87 (1H, m); 3.86-3.72 (1.5H, m); 3.69-3.27 (4H, m); 2.73-2.60 (0.5H, m); 2.46-2.08 (4.5H, m) is APCI-MS: m/z 450.1 [MH+] Example 200 N-(5-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide 20 The compound was prepared analogously to Example 197. APCI-MS: m/z 481.2, 483.2 [MH+] 25 Example 201 4-Acetylamino-3-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} benzoic acid methyl ester The compound was prepared analogously to Example 197. 30 WO 01/62728 PCT/SEO1/00403 101 APCI-MS: m/z 497.1, 499.2 [MH+] Example 202 N-(3-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen 5 2-yl)-acetamide The compound was prepared analogously to Example 197. APCI-MS: m/z 489.2, 491.2 [MH+] 10 Example 203 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-cyano-phenyl) acetamide 15 The title compound was prepared according to the method in Example 197. APCI-MS: m/z 430.2 [MH+] Example 204 4-Acetylamino-3-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} 20 benzoic acid methyl ester The compound was prepared analogously to Example 197. APCI-MS: m/z 463.2 [MH+] 25 Example 205 N-(3-{3- [3-(4-Chloro-phenoxy)-pyrrolidin-1-ylI-2-hydroxy-propoxy}-naphthalen-2 yl)-acetamide 30 The title compound was prepared according to the method in Example 197.
WO 01/62728 PCT/SEO1/00403 102 APCI-MS: m/z 455.2 [MH+] Example 206 5 N-(5-Cyano-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide The title compound was prepared according to the method in Example 197. to APCI-MS: m/z 478.2 480.1 [MH+] Example 207 N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5 trifluoromethyl-phenyl)-acetamide 15 The title compound was prepared according to the method in Example 197. APCI-MS: m/z 521.1 523.2 [MH+] 20 Example 208 N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide trifluoroacetate The title compound was prepared according to the method in Example 197. 25 APCI-MS: m/z 423.1, 424.9 [MH*] Example 209 N-(5-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) 30 acetamide trifluoroacetate WO 01/62728 PCT/SEO1/00403 103 i) N-(5-Acetyl-2-oxiranylmetoxy-fenyl)-acetamide To a solution of 4-acetyl-2-nitrophenol (0.50g, 2.76mmol) in THF (20 ml) was added 10% Pd/C (0.15g). The resultant mixture was hydrogenated with H 2 at 1 atm for 5 hours and 5 was then filtered through celite and evaporated to give 0.63g of a red oil. Water (20 ml) and acetic anhydride (0.35g, 3.44mmol) was added and the mixture was stirred vigorously for 5 minutes. The reaction mixture was then heated with stirring to 60'C for 30 minutes, and was then allowed to cool. A red solid was formed and the precipitate was collected by filtration, washed with water and dried to give 0.27g (1.40mmol) of N-(5-Acetyl-2 10 hydroxy-phenyl)-acetamide. This was dissolved in DMF (5ml). K 2 C0 3 (0.34g, 2.45mmol) and epibromohydrin (0.21 g, 1.54mmol) was added and the resulting mixture was heated with stirring at 50*C for 3 hours. The mixture was partitioned between EtOAc and water 40+40ml. The organic phase was washed twice with water and once with brine and finally concentrated in vacuo to give a red oil. The crude product was purified on silica is (Heptane/EtOAc, 1:2-1:4) to give 110 mg (16%) of the subtitle compound. H-NMR (400MHz, CDCl 3 ): 5 9.03 (1H, d, J1.9Hz), 7.81 (1H, bs), 7.74 (1H, dd, J8.6, 2.3Hz), 6.96. (1H, d, J8.6Hz), 4.48 (1H, dd, J11.3, 2.4Hz) 4.00 (1H, dd, J11.4, 6.4Hz), 3.45 3.40 (1H, m), 2.99 (1H, t, J4.4Hz), 2.79 (1H, dd, J4.7, 2.6 Hz), 2.59 (3H, s), 2.26 (3H, s). 20 ii) N-(5-Acetyl-2-{3-{3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide trifluoroacetate The title compound was prepared according to the method described in Example 197. 25 APCI-MS: m/z 447, 449 [MH*] Example 210 N-(2-{3-{3-(4-Chlorophenoxy)-1-pyrrolidinyl-2-hydroxypropoxy}phenyl) methanesulfonamide 30 WO 01/62728 PCT/SEO1/00403 104 i) 1-(2-Aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyll-2-propanol dihydrochloride A mixture of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2 hydroxypropoxy}phenyl)acetamide (0.95 g, 2.34 mmol) and concentrated hydrochloric 5 acid (25 mL) was heated (100 -105 'C) for 3 hours then allowed to stand at room temperature overnight. The mixture was concentrated at reduced pressure to a third of its volume basified with saturated sodium hydrogen carbonate. The resulting suspension was extracted twice with ethyl acetate. The organic extracts were dried, the solvent was evaporated at reduced pressure to give a pale brown oil. This oil was dissolved in a to minimum amount of methanol, diluted with ethyl ether and the product precipitated by addition of HCl-saturated ethyl ether. The product was filtered to afford the subtitle product (0.93 g, 91.2%). APCI-MS: m/z 363 [MH*] for the free base. 15 ii) N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl) methanesulfonamide Methanesulfonyl chloride (35 mg, 0.3 mmol) was added to cold (0 C), stirred mixture of the above amine (110 mg, 0.25 mmol) and pyridine (0.4 mL) in dry dichloromethane (10 20 mL). The mixture was then stirred at room temperature for 1.5 hour then concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was concentrated and the residue was purified by flash chromatography (silica gel, dichloromethane-methanol, 25:1) to afford the title compound (68 mg, 61.8%) as a foam. 25 'H-NMR (400MHz, CDC1 3 ): 5 7.51 (dd, 1H, J= 1.4 and 8.0 Hz), 7.22 (m, 2H), 7,10 (m, 1H), 7.68 (m. 1H), 6.92 (d, 1H, J= 9.0 Hz), 6.76 (m, 2H), 5.78 (very bs, 1H), 4.80 (m, 1H), 4.20 (m, 1H), 4.08 (m, 1H), 3.98 (m,1H), 3.16 (m, 1H), 3.01 (m, 1H), 2.96 (s, 3H), 2.89 (m, 2H), 2.74 (m, M), 2.68 (dd, 1H, J= 4.0 and 12.2 Hz), 2.3 (m, 1H), and 2.02 (m, 1H).
WO 01/62728 PCT/SEO1/00403 105 "C-NMR,400 MHz, CDC1 3 ): 6 155.9, 149.4, 129.4, 126.9, 125.8, 125.77, 125.75, 122.29, 122.26, 12217, 115.5, 113.52, 113.50, 76.52, 76.49, 72.15, 72.09, 67.18, 67.08, 60.24, 60.07, 57.96, 57.94, 53.18, 52.98, 39.1, 31.92, 31.90. 5 APCI-MS: m/z 441[MH*]. Example 211 N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrodinyll-2-hydroxypropoxyl phenyl)urea 10 i) N-(5-Chloro-2-hydroxyphenyl)urea A solution of potassium cyanate (6.14 g, 75.6 mmol) in water (50 mL) was added dropwise to a stirred suspension of 2-amino-4-chlorophenol (5.00 g, 34.8 mmol) in a mixture of acetic acid (350 mL) and water (250 mL) and the resulting solution was stirred at room 15 temperature for 3 hours. The reaction mixture was extracted three times with ethyl ether. The ether extracts were combined and concentrated to a thick oil. A 10% solution of sodium hydrogen carbonate (250 mL) was added to the above oil. The solid product was filtered and washed several times with water and recrystallized (toluene containing a little methanol) to afford the subtitle compound (3.27 g, 50.4%) 20 'H-NMR (400MHz, DMSO-d6): 6 10.1 (s, 1H), 8.07 (d, 1H, J=2.2 Hz), 8.04 (s, 1H), 6.75 6.78 (m, 2H), 6.29 (bs, 2H). "C-NMR: 6156.0, 144.1, 130.0, 122.5, 120.2, 117.5, 115.2. 25 ii) N-[5-Chloro-2-(2-oxiranylmethoxy)phenyllurea A suspension of N-(5-chloro-2-hydroxyphenyl)urea (53 mg, 0.28 mmol), cesium carbonate (92 mg, 0.28 mmol) and epibromohydrine (49 mg, 0.36 mmol) in dry DMF (0.6 mL) was stirred at room temperature for 24 hours. The mixture was then partitioned between ethyl 30 acetate and water. The organic phase was washed with water three times, dried and WO 01/62728 PCT/SEO1/00403 106 concentrated to a solid residue. This crude product was recrystallized (ethyl ether and heptane to afford the subtitle compound (18 mg, 26.5%). 'H-NMR (400MHz, DMSO-d6): 6 8.20 (d, IH, J=2.2 Hz), 8.00 (s, 1H), 7.00 (d, 1H, J=8.8 5 Hz), 6.88 (dd, 1H, J= 2.4 and 8.6 Hz), 6.40 (bs, 2H), 4.40 (dd, lH, J= 2.2 and 12.0 Hz), 3.90 (dd, 1H, J= 6.6 and 12.0 Hz), 3.37 (m, 1H), 2.88 (t, 1H, H= 4.8 Hz), 2.74 (m, 1H). iii) N-(5-Chloro-2-[3-13,4-dichlorophenoxy)-1-pyrrodinyl]-2-hydroxypropoxyl phenyl)urea 10 A solution of the subtitle compound (ii) (16 mg, 0.07 mmol) and 3-(3,4 dichlorophenoxy)pyrrolidine (17 mg, 0.07 mmol) in absolute ethanol (1 mL) for 2 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (dichloromethane-methanol, 15:1) to afford the title compound (11 mg, 33%). 15 'H-NMR (400MHz, DMSO-d6): 6 8.18 (d, 1H, J= 2.6 Hz), 7.94 (s, 1H), 7.5 (d, 1H, J= 0.0Hz), 7.16 (d, 1H, J= 2.1 Hz), 6.82-6.98 (m, 3H), 6.33 (bs, 2H), 4.98 (m, 1H), 4.90 (m, 1H), 3.85-4.07 (m, 3H), 2.63-2.93 (m, 5H), 2.21-2.30 (m, 1H), 1.74 (m, 1H). 20 APCI-MS: m/z 198 [MH*] Example 212 1-(3-{2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate 25 i) N-(2-Hydroxyphenyl)urea A solution of potassium cyanate (3.94 g, 48.6 mmol) in water (30 mL) was added during 15 min. to suspension of 2-aminophenol (2.41 g, 22.1 mmol) in 50% aqueous acetic acid (160 mL). The resulting solution was allowed to stand at room temperature overnight and 30 then extracted with ethyl ether (3 times). The combined organic extracts was concentrated WO 01/62728 PCT/SEO1/00403 107 to small volume and poured into cold saturated aqueous sodium hydrogen carbonate. The solid was filtered and washed with water to afford the subtitle compound (1.61 g, 47.9%). s 'H-NMR (400MHz, DMSO-d 6 ): 6 9.88 (s, 1H), 7.97 (s, 1H), 7.80 (bd, 1H), 6.77 (m, 1 H), 6.68 (m, 1H), 6.17 (s, 2H), ii) N-[2-(2-Oxiranylmethoxy)phenyllurea A solution of epibromohydrin (0.94 g, 6.84 mmol) in dry DMF (2mL) was added dropwise to to a stirred suspension of N-(2-hydroxyphenyl)urea (0.65 g, 4.27 mmol) and cesium carbonate (2.22 g, 6.84 mmol) in DMF (8 mL). After 2 hours the mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water (3 times), dried and concentrated. The semi-solid residue was disssolved in dichloromethane/ethyl ether, filtered and heptane was is added to turbidity. After standing at room temperature overnight, the solid was filtered to afford the subtitle compound (0.28 g, 32%). 'H-NMR (400MHz, DMSO-d 6 ): 6 8.07(m, 1H), 7.82 (s, 1H), 6.97 (m, 1H), 6.85 (m, 2H), 6.24 (bs, 2H), 4.37 (dd, 1H, J=2,5 and 11.6 Hz), 3.89 (dd, 1H, J=6.4 and 11.6 Hz), 3.38 (m, 20 1H), 2.87 (t, 1H, J=4.6 Hz), 2.75 (dd, 1H, J=2.6 and 5.2 Hz). APCI-MS: m/z 209 [MH*]. iii) 1-(3-{2-[(Aminocarbonyl)aminolphenoxy}-2-hydroxypropyl)-3-(4 25 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate A solution of N-[2-(2-oxiranylmethoxy)phenyl]urea (78 mg, 0.37 mmol) and 3-(4 chlorophenoxy)pyrrolidine (70 mg, 0.36 mmol) in absolute ethanol (4 mL) was heated at reflux for 2.5 hours. The mixture was then concentrated and the residue was purified by HPLC to afford the title compound (102 mg, 54.5%). 30 WO 01/62728 PCT/SEO1/00403 108 'H-NMR (400MHz, DMSO-d 6 + D 2 0): 6 7.98 (bd, 1H, J=7.2 Hz), 7.36 (d, 2H, J=8.8 Hz), 6.95-7.02 (m, 3H), 6.88 (m, 2H), 5.15 (bd, IH). 4.26 (m, 1H). The remaining 10 aliphatic protons appear as complicated overlapping multiplets between 6 2.04 and 4.04. 5 APCI-MS: m/z 406 [MH*] and 408 [MH*+2] for the free base. Example 213 1-(3-{2-{(Aminocarbonyl)aminophenoxy}-2-hydroxypropyl)-3-(3,4 dichlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate 10 . A solution of N-[2-(2-oxiranylmethoxy)phenyl]urea (Described under example 22, step ii; 69 mg, 0.33 mmol) and 3-(3,4-dichlorophenoxy)pyrrolidine (77 mg, 0.33 mmol) in absolute ethanol (4.5 mL) was heated at 70'C for 2 hours. The residue after evaporation of the solvent was purified by HPLC to afford the title compound (133 mg, 72.3%). 15 'H-NMR (400MHz, DMSO-d 6 + D 2 0): 6 7.96 (bd, 1H, J=7.4 Hz), 7.54 (bd, 1H, J=9.0 Hz), 7.27 (bs, 1H), 6.84-7.00 (m, 4H), 5.20 (bd, 1H), 4.26 (m, 1H). The remaining 10 aliphatic protons appear as complicated overlapping multiplets between 6 2.05 and 4.03. 20 APCI-MS: m/z 439.9 [M] and 442 [M+2] for the free base. Example 214 1-(3-{2-[(Aminocarbonyl)aminol-4-chlorophenoxy}-2-hydroxypropyl)-3-(4 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate 25 A solution of N-[2-(2-oxiranylmethoxy)phenyl]urea (described under Example 212, step ii; 47 mg, 0.22 mmol) and 3-(4-chlorophenoxy)pyrrolidine (41 mg, 0.2 mmol) in absolute ethanol (3 mL) was heated at 70"C for 1.5 hours. The solvent was then evaporated and the residue was purified by HPLC to afford the title compound (67 mg, 60.9%). 30 WO 01/62728 PCT/SEO1/00403 109 'H-NMR (400MHz, CD 3 OD): 5 8.04(s, 1H), 7.31 (d, 2H, J=8.6 Hz), 6.94-6.98 (m, 4H), 5.20 (bs, 1H), 4.40 (m, 1H). The remaining 10 aliphatic protons appear as complicated overlapping multiplets between 5 2.25 and 4.13. 5 APCI-MS: m/z 440.1 [M] and 442.1 [M+2] for the free base. Example 215 N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxypropoxy}phenyl)-N' ethylurea hydrochloride 10 An ether solution of N-(2- {3-[3-(4-chlorophenoxy)- 1 -pyrrolidinyl]-2 hydroxypropoxy}phenyl)urea [obtained from the hydrochloride (110mg, 0.25mmol) by treatment with 1M NaOH and extraction with ether] was treated with ethyl isocyanate (1 6pl, 0.2mmol) in a sealed vial for 15h at ambient temperature. After evaporation and 15 purification by flash chromatography on silica (EtOAc/MeOH 100/5) the appropriate fractions were acidified with 1M HCl and lyophilized from acetic acid to give the title compound as a white amorphous solid (35mg, 37%). The substance is a mixture of two diastereomeric pairs. 20 APCI-MS: m/z 434 [MH*] Example 216 N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N' methylurea hydrochloride 25 To a solution of N-(2-{3-[3-(4-chlorophenoxy)- 1 -pyrrolidinyl]-2 hydroxypropoxy}phenyl)urea [obtained from the hydrochloride (44mg, 0.lmmol) by treatement with IM NaOH and extraction with ether] in DCM (3ml) di(tert-butyl) tricarbonate (26mg, 0. 1mmol) was added, and the solution was set aside for 15 min.
WO 01/62728 PCT/SEO1/00403 110 Methylamine (2M in DCM, 100pl, 0.2mmol) was added and the solution was left to stand over night. After evaporation the crude product was purified by preparative RP-HPLC using acetonitrile and water containing 0.1% TFA as mobil phase. The appropriate fraction was concentrated in vacuo and extracted with 1M NaOH and ether. s The residue from the organic phase was acidified with 1M HC1 and lyophilized from acetic acid to afford the title compound as a white amorphous solid (15mg, 30%). The substance is a mixture of two diastereomeric pairs. APCI-MS: m/z 420 [MH*] 10 Example 217 (2S,4S)-1-{3-{2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2 pyrrolidinecarboxylic acid; compound with trifluoroacetic acid 15 (i) Methyl (2S,4S)-1-{3-{2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(4 chlorophenoxy)-2-pyrrolidinecarboxylate hydrochloride Methyl (2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylate (370mg, 1.Ommol) and N [2-(2-oxiranylmethoxy)phenyl]acetamide (207mg, 1.0mmol) dissolved in tert-butanol (7ml) was stirred in a sealed vial at 100*C over night. Workup of the crude material by flash 20 chromatography on silica (DCM/MeOH 100/2), acidification of the appropriate fractions with 1 M HCl and lyophilization from acetic acid afforded the subtitled compound as a white amorphous solid (360mg, 72%). The substance is a diastereomeric mixture. APCI-MS: m/z 463 [MH*] 25 ii) (2S,4S)-1-{3-{2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2 pyrrolidinecarboxylic acid; compound with trifluoroacetic acid Compound (i) (50mg, 0.1mmol) was dissolved in acetonitrile (2ml) and water (3ml). Lithium hydroxide hydrate (8mg, 0.2mmol) dissolved in water (0.5ml) was added. The 30 reaction was complete after 0.5h as determined by analytical HPLC. The mixture was WO 01/62728 PCT/SEO1/00403 111 acidified with TFA and purified by preparative RP-HPLC using acetonitrile and watef containing 0.1% TFA as mobile phase. The appropriate fraction was concentrated in vacuo and the residue lyophilized from acetic acid to give the title compound as a white amorphous solid (27mg, 48%). The substance is a diastereomeric mixture. 5 APCI-MS: m/z 449 [MH*], 431 [MH*, lactone, minor amount] Example 218 Ethyl (2S,4S)-1-{3-[2-(acetylamino)phenoxyl-2-hydroxypropyl}-4-(3,4 10 dichlorophenoxy)-2-pyrrolidinecarboxylate; trifluoroacetic acid salt i) Methyl (2S,4S)-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylate The compound was prepared by analogy with Example 217(ii) from N-Boc-cis-4-hydroxy L-proline methylester and 3,4-dichlorophenol. 15 'H-NMR (400MHz, DMSO-d6): 6 9.64 (bs, 2H); 7.58 (d, 1H); 7.25 (d, 1H); 6.94 (dd, 1H); 5.24 (m, 1H); 4.66 (dd, 1H); 3.76 (s, 3H); 3.55 (dd, 1H); 3.47 (d, 1H); 2.67-2.58 (m, 1H); 2.38 (d, 1H) 20 APCI-MS: m/z 290, 292 [MH*, isotope pattern] ii) Ethyl (2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4 dichlorophenoxy)-2-pyrrolidinecarboxylate; trifluoroacetic acid salt The compound was prepared by analogy with Example 217 from compound i) (404mg, 25 1.0mmol) and N-[2-(2-oxiranylmethoxy)phenyl]acetamide (207mg, 1.Ommol), with the exception that ethanol was used as solvent. Reesterification occurred, and after work-up and purification the title compound was isolated as a white solid (209mg, 33%). The substance is a diastereomeric mixture. 30 APCI-MS: m/z 511, 513 [MH*, isotope pattern] WO 01/62728 PCT/SEO1/00403 112 Example 219 N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl-2 hydroxypropyl}oxy)phenyl]acetamide; trifluoroacetic acid salt and 5 N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2 hydroxypropyl}oxy)phenylacetamide; trifluoroacetic acid salt i) [(2S,4S)-4-(4-Chlorophenoxy)pyrrolidinyllmethanol Methyl (2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylate 10 (prepared from cis-4-hydroxy-L-proline methylester according to Example 217ii)) (850 mg, 3.32 mmol) in dry THF (20 ml) was added during 40 min to a mixture of lithium aluminiumhydride (505 mg, 13.3 mmol) in dry THF (10 ml) at 0*C under an argon atmosphere. After stirring overnight at room temperature sodium sulfate decahydrate (1 g) was added, followed by dropwise addition of water (0.5 ml), sodium hydroxide (15% w/v, i5 0.5 ml) and water (1.5 ml). Filtration and evaporation gave a syrup which was purified by flash chromatography on silica gel (dichloromethane/methanol/concentrated ammonia 100/20/1) to give the subtitle compounds (0.60 g, 79%). 1 H-NMR (400 MHz, CDC13): 6 7.22 (m, 2H), 6.78 (in, 2H), 4.79 (in, 1H), 3.62 (in, 2H), 20 3.39 (in, 1H), 3.23 (bd, 1H), 3.14 (dd, 1H, J5.0 Hz, 12.2 Hz), 2.28 (m, 1H), 1.72 (in, 1H). MS-APCI+: m/z 228 [MH*] ii) N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2 25 hydroxypropyl}oxy)phenyllacetamide; trifluoroacetic acid salt and N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl-2 hydroxypropyl}oxy)phenyllacetamide; trifluoroacetic acid salt [(2S,4)-4-(4-Chlorophenoxy)pyrrolidinyl]methanol (380 mg, 1.67 mmol) and N-[2-(2 30 oxiranylmethoxy)phenyl]acetamide (414 mg, 2.00 mmol) were dissolved in tert-butanol (5 WO 01/62728 PCT/SEO1/00403 113 ml) and stirred in a sealed vial at 1004C for 3h. The solution was concentrated and the residue was purified by flash chromatography on silica gel (dichloromethane/methanol 13/1) followed by preparative RP-HPLC using acetonitrile/water containing 0.1% trifluoroacetic acid as mobile phase. The appropriate fractions were lyophilized to give the s title compounds (epimer A: 248 mg, 27 %, epimer B: 115 mg, 13 %; stereochemistry at epimeric centre not determined). Epimer A: 1H-NMR (400 MHz,MeOD): 6 7.82 (dd, 1H, J 1.3 Hz, 8.0 Hz), 7.31 (m, 2H), 7.14 (in, io 1H), 7.04 (m, 1H), 6.96 (m, 3H), 5.20 (m, IH), 4.40 (m, IH), 4.11 (bd, 2H), 3.79-4.05 (m, 5H), 3.73 (dd, 1H, J5.2 Hz, 12.5 Hz), 3.43 (dd, 1H, J2.6 Hz, 13.0 Hz), 2.80 (in, 1H), 2.18 (s, 3H), 2.12 (m, 1H). MS-APCI+: m/z 435 [MH*] 15 Epimer B: IH-NMR (400 MHz,MeOD): 5 7.79 (dd, IH, J 1.3 Hz, 7.9 Hz), 7.32 (in, 2H), 7.14 (m, 1H), 7.04 (m, 1H), 6.97 (m, 3H), 5.18 (m, 1H), 4.49 (m, 1H), 3.83-4.19 (in, 7H), 3.69 (dd, 1H, J4.8 Hz, 13.2 Hz), 3.34 (m, 1H), 2.72 (m, 1H), 2.18 (s, 3H), 2.07 (m, 1H). MS-APCI+: m/z 435 [MH*] 20 Example 220 N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxy-2 methylpropoxy}phenyl)acetamide hydrochloride 25 i) N-{2-{(2-Methyl-2-propenyl)oxy]phenyl}acetamide The compound (1.74 g, 85 %) was prepared from 3-chloro-2-methylpropene (1.09 g, 11.9 mmol) and 2-acetamidophenol (1.50 g, 9.92 mmol) analogously to that described in Example 8(i).
WO 01/62728 PCT/SEO1/00403 114 1 H-NMR (400 MHz, CDC13): 8 8.36 (dd, IH, J1.7 Hz, 7.8 Hz), 7.80 (bs, 1H), 6.98 (m. 2H), 6.87 (dd, 1H, J 1.6 Hz, 7.9 Hz), 5.08 (s, 1H), 5.04 (s, 1H), 4.51 (s, 2H), 2.21 (s, 3H), 1.85 (s, 3H). 5 ii) N-{2-{(2-Methyl-2-oxiranyl)methoxy]phenyl}acetamide The compound (0.56 g, 65 %) was prepared from N-{2-[(2-methyl-2 propenyl)oxy]phenyl}acetamide (800 mg, 3.90 mmol) and m-chloroperbenzoic acid (80 %, 1.10 g, 5.22 mmol) analogously to that described in Example 8 (ii). 10 1H-NMR (400 MHz, CDC13): 6 8.36 (m, 1H), 8.01 (bs, 1H), 7.01 (m, 2H), 6.91 (m, 1H), 4.07 (m, 2H), 2.96 (d, 1H, J4.8 Hz), 2.79 (d, 1H, J4.8 Hz), 2.22 (s, 3H), 1.49 (s, 3H). iii) N-(2-{3-13-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxy-2 methylpropoxy}phenyl)acetamide hydrochloride 15 The title compound (255 mg, 110 %) was prepared from N-{2-[(2-methyl-2 oxiranyl)methoxy]phenyl}acetamide (123 mg, 0.557 mmol) and 3-(4 chlorophenoxy)pyrrolidine (100 mg, 0.506 mmol) analogously to that described in Example 1 (iii). 20 1 H-NMR (400 MHz, MeOD): 5 7.61 (m, IH), 7.29 (m, 2H), 7.18 (m, 1H), 7.10 (m, 1H), 6.96 (m, 3H), 5.18 (m, 1H), 3.91-4.22 (m, 4H), 3.37-3.76 (m, 4H), 2.66 (m, 2 H), 2.37 (m, 1H), 2.25 (m, 2 H), 2.15 (m, 3H), 1.45 (m, 3H). MS-APCI+: m/z 419 [MH] 25 General procedures and preparation of starting materials for Examples 221-230 Preparation of the epoxides: 30 A) N-(2-{ [(2S*,3S)-3-MethyloxiranylImethoxy}phenyl)acetamide WO 01/62728 PCT/SEO1/00403 115 i) N-{2-[(E)-1-Propenyloxyjphenyl}acetamide A heterogenic mixture of commercially available 1-chloro-2-butene (Aldrich, predominantly trans) (453 mg, 0.49 mL, 5.00 mmol), 2-acetamidophenol (756 mg, 5.00 5 mmol) and potassium carbonate (691 mg, 5.00 mmol) in aceton (10 ml) was heated to reflux over night. After evaporation of the solvent the residue was taken up by ethylacetate and water. Washing of the organic phase with water, 5-proz. sodium hyroxide and brine and evaporation of the solvent afforded the crude which was purified by flash chromatography on silica gel (heptane/EtOAc = 3:2). Yield: 732 mg (71 %) of a brownish 10 yellow solid.Trans: cis = 81:19 (ratio determined by 'H-NMR; 400MHz, CDC 3 ): MS-APCI+: m/z 206.1 [MH+]. ii) M-chloroperbenzoic acid (70-proz.; 270 mg, 1.92 mmol, 2.0 equiv.) was added to a is ice bath cooled solution of compound i) (112 mg, 546 pmol) dissolved in dichloromethane (3 ml) and stirred without further cooling over night. After addition of ethylacetate the mixture was washed with sat. sodium sulfite, 5-proz. sodium hyroxide and brine. Drying over sodium sulfate, evaporation of the solvent and flash chromatography on silica gel afforded 86 mg (71 %) of the product as a beige solid in a trans:cis-ratio of 83:17 as 20 determined by 'H-NMR. 'H-NMR (400MHz, CDCl 3 ; only the signals of the major isomer are given): 8 8.35 (1H, m), 7.90 (1H, br.s), 7.00 (2H, m), 6.88 (1H, m), 4.30 (1H, dd, J 11.4, 2.5Hz), 3.96 (1H, dd, J 11.4, 5.7Hz), 3.08 (2H, m), 2.21 (3H, s), 1.40 (3H, d, J 5.2Hz). 25 MS-APCI+ : m/z 222.1 [MH+]. B) N-(2-{ [(2S,3R)-3-Methyloxiranyl]methoxy}phenyl)acetamide 30 i) N-12-(2-Butynyloxy)phenyllacetamide WO 01/62728 PCT/SEO1/00403 116 A mixture of 1-bromo-2-butine (1.39 g (10.4 mmol), 2-acetamidophenol (1.58 mg, 10.4 mmol), anhydrous potassium carbonate (1.44 g, 10.4 mmol) and sodium iodide (30 mg) in butanone (50 ml) was heated over night to reflux. After that the reaction mixture was filtrated, the filtrate was evaporated and the resulting residue was taken up by ethyl acetate. s The obtained solution was washed with 5-proz. sodium hydroxide, brine and water, dried over sodium sulfate and evaporated. The crude was recrystallized out of heptane/MTB (1:1) yielding in 1.57 g (74 %) of a light brown needles. MS-APCI+: m/z 204.1 [MH+]. 10 ii) N-{2-[(Z)-2-Butenyloxylphenyl}acetamide A mixture of the alkyne i) (357 mg, 1.76 mmol) and 5-% Pd/BaSO 4 (22 mg) in pyridine (2.0 mL) was hydrogenated for 2h 30min under atmospheric pressure at room temperature. At this point the starting material was completely consumed, but some overreduction to the 15 corresponding alkane was observed by LC/MS. The reaction mixture was filtered on celite which was thoroughly washed with ethylacetate. Thereafter the filtrate was washed with 1 N HCl to acidic reaction and finally washed neutral with brine. Drying over sodium sulfate, evaporation of the solvent yielded in 318 mg (88 %) crude which contained beside the desired Z-olefin also some E-olefine and corresponding alkane as biproducts. The ratio as 20 determined by 'H-NMR (400MHz, CDCl 3 ) was E: Z: alkane = 83 :10: 7. The crude was used in the next step without further purification. MS-APCI+ : m/z 206.1 [MH+]. 25 iii) The olefine ii) (310 mg, 1.51 mmol)was dissolved in dichloromethane (10 ml) and m-chloroperbenzoic acid (80-proz.; 587 mg, 2.72 mmol, 1.8 equiv.) was added at 0 0 C. Stirring over night at ambient temperature was followed by evaporation of the solvent and taking up the resulting residue with ethylacetate, washing with sat. sodium sulfite, 5-% sodium hydroxide and brine and drying over sodium sulfate. Evaporation of the solvent 30 and flash chromatography on silica gel (ethylacetate/heptane = 2:1 continued to WO 01/62728 PCT/SEO1/00403 117 ethylacetate) gave 269 mg (81 %) of the epoxide in a E:Z-ratio of 82:18 (determined by 'H NMR) as a white powder. 'H-NMR (400MHz, CDCl 3 ; only the signals of the major isomer are given): 8 8.37 (1H, dd, 5 J 7.5, 2.1Hz), 7.81 (1H, br.s), 7.02 (2H, m), 6.91 (1H, dd, J 7.4, 1.7Hz), 4.32 (IH, dd, J 11.1, 3.6Hz), 4.03 (1H, dd, J 11.1, 6.9Hz), 3.33 (1H, dt, J 7.0, 4.0Hz), 3.24 (iH, dt, J 9.9, 5.5Hz), 2.21 (3H, s), 1.38 (3H, d, J 5.7Hz). MS-APCI+ : m/z 222.1 [MH+]. 10 C) N-{2-[(1R,2S,5R)*-6-Oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide i) (2-Cyclopenten-1-yloxy)(triisopropyl)silane A solution of 2-cyclopentenol (K. Alder, F. H. Flock, Chem. Ber. 1956, 89, 1732.) (2.31 g, is 27.5 mmol), (triisopropyl)chlorsilane (5.30 g, 5.9 mL, 27.5 mmol), imidazole (2.06 g, 30.2 mmol) in DMF (50 mL) was stirred at room temperature for 3h and for an additional hour. at 50 C. Then the solution was diluted with ethylacetate, washed 4 times with water and dried over sodium sulfate. Evaporation of the solvent yielded in 6.32 g (96 %) of the silylether 513/13 as a colourless liquid. No major impurities were visible in the 'H-NMR 20 spectrum. 'H-NMR (400MHz, CDC1): 6 5.88 (1H, m), 5.76 (1H, m), 4.98 (1H, m), 2.48 (1H, m), 2.27-2.17 (2H, m), 1.70 (iH, m), 1.12-1.05 (21H, m). 25 II) Triisopropyl[(1R,2R,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]silane M-chloroperbenzoic acid (70-%.; 5.41 g, 21.9 mmol, 1.7 equiv.) was added to a ice bath cooled solution of compound i) (3.10 g, 12.9 mmol) dissolved in dichloromethane (25 ml) and stirred without further cooling additional 90 min. After filtration of the reaction mixture, evaporation of the filtrate the residue was dissolved in ethylacetate, washed with 30 sat. sodium sulfite, 5-proz. sodium hydroxide and brine and dried over sodium sulfate.
WO 01/62728 PCT/SEO1/00403 118 Evaporation of the solvent afforded the crude as a mixture of the diastereomeric epoxides in trans/cis-ratio of 78:22 ('H-NMR). Separation by flash chromatography on silica gel (heptane/ethylacetate = 95:5 continued to 90:10) afforded 1.65 g (50 %) of the desired trans-epoxide (IR,2R,5R)* as the first eluated diastereomer. The total yield of both 5 diastereomeric epoxides was 2.86 g (87 %). 'H-NMR (400MHz, CDC1 3 ): 8 4.39 (1H, d, J 3.4Hz), 3.54 (1H, d, J 2.5Hz), 3.37 (1H, d, J 2.5Hz), 1.94 (1H, m), 1.84 (dtd, J 13.7, 9.3, 1.1Hz), 1.60-1.55 (2H, m), 1.13-1.04 (21H, m). to iii) (1S,2R,5R)*-6-Oxabicyclo[3.1.0]hexan-2-ol To a solution of the silylether ii) (280 mg, 1.09 mmol) in THF (2.0 mL) tetrabutylammonium fluorid (1.0 M in THF; 1.2 mL, 1.20 mmol) was added. After stirring for 3 h at room temperature the mixture was diluted with ethylacetate, washed with brine and dried over sodium sulfate. Chromatographic filtration on silica gel 15 (heptane/tertbutylmethylether 2:1 continued to ethylacetate) afforded 79 mg (72 %) as a pale yellow oil. 'H-NMR (400MHz, CDCl 3 ): 5 4.36 (lH, d, J 5.1Hz), 3.55 (1H, s), 3.42 (1H, d, J 1.5Hz), 1.99 (1H, m), 1.84 (1H, dddd, J 13.9, 10.1, 9.0, 1.1Hz), 1.69-1.53 (3H, m). 20 iv) The title compound was prepared according to the general protocol (I) below. 'H-NMR (400MHz, CDC1 3 ): 5 8.38 (1H, m), 7.91 (1H, br.s), 7.02-6.98 (2H, m), 6.94 (1H, m), 4.78 (1H, td, J 8.0, 1.2Hz), 3.61 (1H, m), 3.54 (1H, d, J 2.7Hz), 2.21 (3H, s), 2.21 (1H, 25 m), 2.10 (1H, dt, J 12.8, 12.0Hz), 1.76 (1H, dtd, J 14.3, 10.4, 1.4Hz), 1.58 (1H, m). MS-APCI+ : m/z 234.1 [MH+]. General protocol (I) for the preparation of N-{2-{(1R,2S,5R)*-6-oxabicyclo(3.1.0]hex 30 2-yloxyjphenyl}acetamides WO 01/62728 PCT/SEO1/00403 119 Step 1 - Mitsunobu coupling: To a ice bath cooled solution of the epoxyalcohol 546/16 (1.0 equiv.), triphenylphosphine (1.2 equiv.) and a 2-nitrophenol (1.0 equiv.) in dry THF (2 mL/mmol) diethyl 5 diazodicarboxylic acid (1.2 equiv.) was added dropwise. Stirring was continued over night without further cooling. Aqueous, basic workup, followed by flash chromatography on silica gel (typical eluant: heptane/ethyl acetate = 1:1) afforded the 2-nitrophenolic esters which contained often an equimolar amount of the biproduct diethyl 1,2 hydrazinedicarboxylate. 10 Step 2 - hydrogenation: A mixture of 2-nitrophenolic esters as obtained from step 1, diisopropyl(dthyl)amine (2.0 equiv.), acetic acid anhydrate (2.0 equiv.) and 5-proz. Pt/C (10 mg/mmol) in ethyl acetate (10 mL/mmol) was hydrogenated for 1h under atmospheric pressure at room temperature. 15 In the case of non-halogenated aromates Pd/C and shorter reaction times, typically about 5 min, could be applied. Thereafter the catalysator was filtered off by a celite filled filterfunnel and washed with ethanol. The filtrate was evaporated and the remaining residue was subjected an aqueous, basic work-up. Subsequent flash chromatography on silica gel (typical eluant: ethyl acetate/heptane = 2:1) afforded the respective acetamides in typical 20 yields of 50-70 % (2 steps). D) N-{5-Chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide Preparation according to protocol (I). 25 'H-NMR (400MHz, CDC 3 ): 6 8.47 (1H, d, J 2.5Hz), 7.89 (1H, br.s), 6.97 (1H, dd, J 8.8, 2.5Hz), 6.85 (1H, d, J 8.8Hz), 4.74 (1H, td, J 8.0, 1.3Hz), 3.58 (1H, m), 3.56 (1H, m), 2.21 (lH, m), 2.21 (3H, s), 2.09 (dt, J 13.0, 7.4Hz), 1.76 (1H, dtd, J 14.3, 10.1, 1.3Hz), 1.56 (lH, m). 30 WO 01/62728 PCT/SEO1/00403 120 MS-APCI+: m/z 268.0 [MH+]. E) N-{4-Fluoro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide 5 Preparation according to protocol (I). 'H-NMR (400MHz, CDCl 3 ): 5 8.23 (1H, dd, J 10.7, 2.8Hz), 7.99 (1H, br.s), 6.89 (1H, dd, J 9.0, 5.5Hz), 6.69 (lH, ddd, J 11.1, 9.0, 3.1Hz), 4.70 (1H, t, J 7.8Hz), 3.56 (2H, s), 2.21 to (1H, dd, J 14.7, 8.4Hz), 2.21 (3H, s), 2.08 (1H, dt, J 13.0, 8.2Hz), 1.75 (1H, dtm, J 14.3, 9.5Hz). MS-APCI+ : m/z 252.1 [MH+]. is General protocol (II) for the addition of aminocycles to substituted 2 (aryloxymethyl)oxiranes Equimolar amounts of aminocycle and epoxide, dissolved in a saturated solution of LiC104 in acetonitrile (1ml/100pmol), were heated to 100*C in a sealed tube. Typical reaction 20 times ranged from 3h for open chained epoxides to 18h for oxabicyclo[3.1.0]hexanes. After cooling down to ambient temperature the reaction mixture was diluted with ethyl acetate and subjected to an aqueous work-up. The crude products were usually obtained in quantitative yields and were purified by flash chromatography on silica gel (typical eluants: ethyl acetate/methanol = 80:20). 25 The Examples 221-230 below were prepared according to the general protocols (I) and (II). Example 221 N-(2-{(1S*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy 30 cyclopentyloxy}-phenyl)-acetamide WO 01/62728 PCT/SEO1/00403 121 'H-NMR (400MHz, CDC1 3 ): 8 8.20 (11H, d, J 7.4Hz), 8.07 (11H, br.s), 7.21 (2H, m), 7.01 6.96 (2H, m), 6.92 (1H, dm, J 7.4Hz), 6.77 (2H, dm, J 8.8Hz), 4.77 (1H, m), 4,54 (1H, br.q, J 4.8Hz), 4.15 (1H, m), 3.04-2.91 (3H, m), 2.81 (1H, q, J 6.8Hz), 2.62 (1H, quint, J 7.3Hz), 5 2.29 (1H, m), 2.16 (3H, s), 2.13-1.90 (5H, m), 1.63 (1H, m). MS-APCI+: m/z 431.2 [MH+]. Example 222 10 N-(2-{(1R*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide 'H-NMR (400MHz, CDC1 3 ): 6 8.26 (1H, m), 7.90 (1H, br.d, J 9.5Hz), 7.20 (2H, m), 6.97 (2H, m), 6.88 (1H, br.d, J 7.3Hz), 6.76 (2H, m), 4.76 (1H, m), 4.50 (1H, m), 4.21 (1H, dt, J is 14.1, 5.5Hz), 3.00-2.89 (3H, m), 2.67-2.54 (2H, m), 2.28 (1H, m), 2.15 (3H, s), 2.11 (1H, m), 1.97 (2H, m), 1.87 (2H, m). MS-APCI+: m/z 431.2 [MH+]. 20 Example 223 N-(2-{(2R*,3R*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-butoxy} phenyl)-acetamide 'H-NMR (400MHz, CDC1 3 ): 6 8.27 ((1H, dd, J 7.6, 1.6Hz), 8.07 (1H, br.s), 7.30 (1H, d, J 25 8.8Hz), 7.04-6.92 (4H, m), 6.74 (1H, dd, J 8.8, 2.9Hz), 4.26 (11H, m), 4.23 (1H, dd J 9.9, 2.7Hz), 4.06 (11H, m), 3.96 (11H, dd, J 9.9, 8.0Hz), 2.86-2.72 (3H, m), 2.58 (11H, m), 2.47 (1H, m), 2.18 (3H, s), 1.99 (2H, m), 1.80 (2H, m), 1.12 (3H, d, J 6.9Hz). MS-APCI+: m/z 469.1 [MH+]. 30 WO 01/62728 PCT/SEO1/00403 122 Example 224 N-(2-{(1S*,2R*,3S*)-3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide s 'H-NMR (400MHz, CDC1 3 ): 8 8.26 (1H, m), 8.20 (1H, br.s), 7.19 (2H, m), 7.02 (2H, m), 6.95 (1H, m), 6.84 (2H, m), 4.49 (1H, q, J 5.2Hz), 4.31 (1H, m), 4.15 (1H, m), 2.95 (2H, q, J 7.8Hz), 2.87 (1H, m), 2.51 (2H, br.q, J 10.2Hz), 2.19 (3H, s), 2.10-1.95 (5H, m), 1.86 (2H, m), 1.60 (1H, m). 10 MS-APCI+: m/z 445.0 [MH+]. Example 225 N-(2-{(2R*,3S*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-butoxy} phenyl)-acetamide 15 'H-NMR (400MHz, CDC1 3 ): 6 8.47 (1H, br.s), 8.36 (1H, dd, J 7.2, 1.3Hz), 7.32 (1H, d, J 9.0), 7.04-6.93 (4H, m), 6.75 (1H, dd, J 9.0, 2.9Hz), 4.34 (1H, m), 4.11 (1H, m), 3.96 (IH, dd, J 10.5, 5.2 Hz), 3.66 (1H, m), 3.00-2.80 (2H, m), 2.71 (2H, m), 2.42 (1H, m), 2.19 (3H, s), 2.05 (1H, m), 1.94-1.81 (2H, m), 1.08 (3H, d, J 6.7Hz). 20 MS-APCI+: m/z 466.9 [MH+]. Example 226 N-(2-{(2R*,3R*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy}-phenyl) 25 acetamide 'H-NMR (400MHz, CDC1 3 ): 6 8.34 (1H, t , J 4.5Hz), 8.18 (1H, br.s), 7.22 (2H, m), 6.99 (2H, m), 6.93 (1H, m), 6.76 (2H, m), 4.78 (1H, m), 4.20 (1H, m), 4.07 (1H, dt, J 10.1, 2.9 Hz), 3.95 (1H, dd, J 10.1, 8.2Hz), 3.15 (0.5H, dd, J 10.7, 6.1Hz), 2.97-2.94 (1.5H, m), 2.89 WO 01/62728 PCT/SEO1/00403 123 (0.5H, q, J 7.6Hz), 2.82 (0.5H, dd, J 10.5, 2.5Hz), 2.73 (0.5H, qm, J 7.5Hz), 2.65 (0.5H, m), 2.58 (1H, m), 2.26 (1H, m), 2.01 (IH, m), 1.09 (3H, appears as dd, J 6.7, 1.7Hz). MS-APCI+ : m/z 419.1 [MH+]. 5 Example 227 N-(2-{(2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy}-phenyl) acetamide 10 'H-NMR (400MHz, CDC1 3 ): 8 8.48 (1H, m), 8.37 (1H, m), 7.22 (2H, m), 7.04-6.93 (3H, m), 6.77 (2H, m), 4.80 (1H, m), 4.12 (1H, m), 3.97 (iH, dd, J 10.5, 5.3Hz), 3.65 (1H, m), 3.09 (0.5H, dd, J 10.3, 6.0Hz), 3.06-2.99 (1.5H, m), 2.94 (0.5H, q, J 8.0Hz), 2.87-2.67 (2.5H, m), 2.25 (1H, m), 2.02 (1H, m), 1.05 (3H, appears as dd, J 6.7, 5.2Hz). 15 MS-APCI+: m/z 418.9 [MH+]. Example 228 N-(2-{(1S*,2R*,3S*)-3-[4-(3-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide 20 'H-NMR (400MHz, CDC1 3 ): 5 8.25 (1H, m), 8.17 (1H, br.s), 7.18 (IH, t, J 8.1Hz), 7.01 (2H, m), 6.97-6.90 (3H, m), 6.79 (1H, dm, J 9.0Hz), 4.48 (1H, q, J 5.5Hz), 4.34 (1H, hept, J 3.5Hz), 4.15 (1H, dd, J 7.2, 5.5Hz), 2.95 (2H, q, J 7.4Hz), 2.87 (1H, m), 2.52 (2H, br.q), J 9.6Hz), 2.19 (3H, s), 2.09-1.94 (6H, m), 1.86 (2H, m), 1.59 (1H, m). 25 -MS-APCI+ : m/z 445.1 [MH+]. Example 229 N-[5-Chloro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl-2 30 hydroxycyclopentyl}oxy)phenyl]acetainde WO 01/62728 PCT/SEO1/00403 124 'H-NMR (400MHz, CDCl 3 ): 6 8.38 (2H, m), 7.31 (1H, d, J 8.7Hz), 6.99 (1H, d, J 8.8Hz), 6.95 (1H, dd, J 8.8, 2.6Hz), 6.86 (lH, d, J 8.8Hz), 6.75 (IH, dd, J 8.8, 2.9Hz), 4.38 (1H, q, J 4.0Hz), 4.31 (1H, hept, J 3.7Hz), 4.10 (1H, dd, J~:7, 6Hz), 3.00 (1H, q, J 7.1Hz), 2.91 5 2.82 (1H, m), 2.53 (2H, m), 2.17 (3H, s), 2.08-1.93 (5H, m), 1.85 (2H, m), 1.60 (1H, m). MS-APCI+: m/z 513.1 [MH+]. Example 230 10 N-[4-Fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2 hydroxycyclopentyl}oxy)phenyllacetamide 'H-NMR (400MHz, CDC1 3 ): 6 8.58 (1H, br.s), 8.19 (1H, dd, J 10.9, 3.2Hz), 7.31 (1.H,.d, J 8.8Hz), 7.00 (1H, d, J 2.9Hz), 6.89 (1H, dd, J 9.0, 5.2Hz), 6.75 (1H, dd, J 9.0, 2.9Hz), 6.67 15 (1H, td, J 8.8, 3.1Hz), 4.35-4.29 (2H, m), 4.09 (1H, dd, J 7.8, 5.0Hz), 3.04 (1H, q, J 7.8Hz), 2.88 (2H, m), 2.54 (2H, m), 2.18 (3H, s), 2.08 (5H, m), 1.85 (2H, m), 1.61 (1H, m). MS-APCI+ :m/z 497.2 [MH+]. 20 Preparation of starting materials for Examples 231-248 A) (S*R*)-1-(3,4-Dichloro-benzyl)-2,5-dimethyl-piperazine A solution of 1,2-dichloro-4-chloromethyl-benzene (1.lml 7.89 mmol) in DMF (5 ml) was added to 2,5-dimethyl-piperazine (1.0g, 8.77 mmol) dissolved in DMF (25 ml). The 25 reaction was stirred over night, poured into a mixture of EtOAc and sodium carbonate (5%). The water phase was washed twice with EtOAc and the combined organic phase once with brine, and dried over sodium sulfate. After evaporation the crude was dissolved in methanol. The dibensylated piperazine does not dissolve. The filtrate was filtered through a short silica column, using methanol as eluant and evaporated to give the pure 30 product. Yield 812mg, 38% WO 01/62728 PCT/SEO1/00403 125 'H-NMR (400MHz, DMSO-d6): 6 7.56 (d, 1H, J= 8.1 Hz), 7.52 (d, 1H, J= 1.8 Hz), 7.20 (dd, 1H, J= 8.2, 1.8 Hz), 3.97 (d, 1H, J= 14.1 Hz), 3.04 (d, 1H, J= 14.2 Hz), 2.76 (dd, 1H, J = 11.9, 3.0 Hz), 2.59 (m), 2.48 (dd, 1H, J = 11.9, 2.6 Hz), 2.37 (t, 1H, J = 10.8 Hz), 2.12 s (m), 1.89 (s), 1.57 (t, 1H, J = 10.4 Hz), 1.00 (d, 1H, J= 6.1 Hz), 0.82 (d, 1H, J = 6.3 Hz). APCI-MS: m/z 273 [M*] B) (S*R*)-1-(4-Chloro-benzyl)-2,5-dimethyl-piperazine 10 Was synthesized in the same way as A) from 1-chloro-4-chloromethyl-benzene (1.27 g, 7.89 mmol) and 2,5-dimethyl-piperazine (1.0g, 8.77 mmol) in DMF. Yield 701 mg, 37% 'H-NMR (400MHz, DMSO-d6): 5 7.36 (d, 2H, J= 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz),_3.97 (d, 1H, J = 13.9 Hz), 3.01 (d, 1H, J = 13.8 Hz), 2.75 (dd, 1H, J = 11.9, 3.0 Hz), 2.57 (m, 15 1H, J = 10.8, 2.6 Hz), 2.47 (dd, 1H, J= 10.9, 2.6 Hz), 2.36 (dd, 1H, J= 11.6, 10.1 Hz), 2.10 (m, 1H), 1.88 (bs, 1H), 1.53 (t, 1H, J = 10.5 Hz), 1.01 (d, 3H, J = 6.1 Hz), 0.80 (d, 3H, J= 6.4 Hz). APCI-MS: m/z 239 [MH*] 20 C) 1-(3,4-Chlorobenzyl)piperazine 3,4-chlorobenzyl chloride (170mg, 0.872mmol) was added to a solution of piperazine (150mg, 1.74mmol) and triethyl amine(lml) in DMF (1Oml) at room temperature. After 2hrs the solution was concentrated in vacuo. The resulting residue was triturated under 25 ether and the obtained solid was washed with water and then dissolved in methanol and co evaporated with toluene to give the product, 89mg, as a solid. APCI-MS: m/z 245, 247[MH*] WO 01/62728 PCT/SEO1/00403 126 'HNMR (400MHz, CD 3 0D) 6 7.41 (d, 1H, J=2.0 Hz), 7.37 (d, 1H, J=8.2 Hz), 7.13 (dd,1H, J=8.2, J=2.0 Hz), 3.5 (s, 2H), 3.05 (m, 4H), 2.57 (m, 4H) D) 1-(4-Chlorobenzyl)piperazine 5 Was prepared by analogy to C) above. Example 231 N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-phenyl)acetamide 10 dihydrochloride A solution of N-acetyl-2-(2,3-epoxypropoxy)aniline (87.53mg, 0.422mmol) and 1-(3,4 chlorobenzyl)piperazine in ethanol (1 Oml 99.5%) was refluxed for 3hrs. The solvent-was distilled off under reduced pressure and the resulting residue was purified by silica gel is column chromatography (dichloromethane/methanol 20:1) to give the title compound as a gum. Addition of 1.OM ethereal HCl solution gave a white solid product 78mg (40%). APCI-MS: m/z 452, 454[MH*] 20 'HNMR (400MHz, CD 3 OD) 8 8.0 (1H, dd, J=1.53Hz, J=8.OlHz), 7.5 (1H, d, J=1.9lHz), 7.45 (lH d, J=8.2Hz), 7.23 (IH, dd, J=6.1Hz, J=2.lHz), 6.89-7.08(4H, m), 4.15(IH, m), 3.9-4.1(2H, m), 3.48(2H, S) 2.45-2.60(10H, m), 2.17(3H, S). Examples 232-248 were synthesized according to Example 231 with the starting 25 materials A) to D) above. Example 232 N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyll-2-hydroxypropoxy}-4 fluorophenyl)acetamide 30 WO 01/62728 PCT/SEO1/00403 127 APCI-MS: m/z 47O[MH'] Example 233 N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl-2 5 hydroxypropoxylphenyl)acetamide APCI-MS: m/z 48O[MH'] Example 234 10 N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinyll-2 hydroxypropoxy} phenyl)acetamide APCI-MS: m/z 486[MH'] 15 Example 235 N-(5-Chloro-2-{3-[4-(3,4-dichloroben-zyl)-2,5-dimethyl-1-piperazinyll-2 hydroxypropoxylphenyl)acetamide APCI-MS: mlz 48O[MH'] 20 Example 236 N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperaznyl-2-hydroxypropoxy}4 methylphenyl)acetamide 25 APCI-MS: m/z 494[MH+] Example 237 N-(2-{3-14-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyll-2-hydroxypropoxy-4 fluorophenyl)acetamide 30 WO 01/62728 PCT/SEO1/00403 128 APCI-MS: m/z 498[MJ-I] Example 238 N-(2-13 [(**--34Dclrbny)25dmty--ieaiyl2 5 hydroxypropoxylphenyl)acetamide APCI-MS: m/z 48OIIMH'] Example 239 to N-(2-{3 f(**--4Clrbny)25dmty--ieaiyl2 hydroxypropoxyl pheuyl)acetamide APCI-MS: mlz 446[MH'I 15 Example 240 N-5Clr-2( (**-4-3,4dichlorobenzyl)2,5dimethylpiperaziyll2-. hydroxypropoxy}phenyl)acetamide APCI-MS: mlz 514[MH'] 20 Example 241 N-(5-Chloro-2-{3- [(S*R *)-4-(4..chlorobenzyl)..2,5-dimethylpiperaznyl..2 hydroxypropoxy} phenyl)acetamide 25 APCI-MS: rn/z 480[MH] Example 242 1-(5-Chloro-2-{3-.f4-(4-chlorobenzoyl)-1-piperazinyll-2-hydroxypropoxy} phenyl)-1 ethanone 30 WO 01/62728 PCT/SEO1/00403 129 APCI-MS: m/z 451 [Mfl'] Example 243 N-5Can- 3-(**)..4.(3,4dichlorobenzyl).2,5-.dnethylpiperazinyl] -2 5 hydroxypropoxylphenyl)acetamide APCI-MS: m/z 5O5[MH'] Example 244 10 N-(2-{3-[(S*R *)..4.(4-.Chlorobenzyl)..2,5-.dimethylpiperazjllyl] -2-hydroxypropoxy}-5 cyanophenyl)acetamide APCI-MS: m/z 471 [MH'] is Example 245 N-(5-Chloro-2-{3-14-(4-chlorobenzyl)-1-piperazinyll-2-hydroxypropoxy} phenyl)acetamide APCI-MS: mlz 452[MH'] 20 Example 246 N-(4-Chloro-2-{3-[4-(4-chlorobenzy1)-2,5-dimethyl-1-piperazinyl]-2 hydroxypropoxylphenyl)acetamide 25 APCI-MS: lz 46O[MH'] Example 247 N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}-5 cyanophenyl)aeetamide 30 WO 01/62728 PCT/SEO1/00403 130 APCI-MS: m/z 457[MH*] Example 248 N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinyll-2-hydroxypropoxy}-4 5 methylphenyl)acetainide APCI-MS: m/z 446[MH*] Example 249 10 N-[5-Chloro-2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyll-2 hydroxycyclopentyl}oxy)phenyl]acetamide MS-APCI+: m/z 464.9 [MH+]. [ct] 22 = - 47.6 (CH 2 C2) 15 Example 250 N-{2-((2S)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4 fluorophenyl}acetamide 20 APCI-MS: m/z 423.1 [M+] Example 251 N-[2-({(2S)-3-[(3S)-3-(4-Chlorobenzyl)pyrrolidinyl-2 hydroxypropyl}oxy)phenyllacetamide hydrochloride 25 i) 3-(4-Chlorobenzyl)pyrrolidine To a solution of 3-(4-chlorobenzyl)-2-pyrrolidinone (420mg, 2mmol) in dry THF (25mL) and under N 2 LAH (190mg, 5mmol) was added in portions with stirring over a period of a couple of minutes. The temperature was increased to 60'C and the stirring continued for 30 2.5h. The mixture was quenched with 200pL water, 200pL 5M NaOH and 600pL water.
WO 01/62728 PCT/SEO1/00403 131 The solid Li- and Al-salts were filtered off and the filtrate was evaporated to give a colourless oil (387mg, 99%). APCI-MS: m/z 196, 198 [MH*] 5 ii) (2S)-1-[3-(4-Chlorobenzyl)-1-pyrrolidinyl]-3-(2-nitrophenoxy)-2-propanol A solution of compound (i) (387mg, 2mmol) and (2S)-2-[(2-nitrophenoxy)-methyl]oxirane (390mg, 2mmol) in ethanol (6mL) was refluxed until the reaction was complete (2h), as determined by LCMS. The solvent was evaporated to give an orange oil (650mg, 83%) 10 which was used without further purification. APCI-MS: m/z 391, 393 [MH*] iii) (2S)-1-(2-Aminophenoxy)-3-[3-(4-chlorobenzyl)-1-pyrrolidinyl-2-propanol is To a solution of compound (ii) (650mg, 1.67mmol) in ethanol (10mL) at 60"C a mixture of tin(II)chloride dihydrate (2.25g, 1Ommol) and 35% hydrochloric acid (2.5mL) was added. The temperature increased rapidly to 75"C. The mixture was stirred at 60"C for further 30 min. After evaporation of the solvent the residue was extracted with 5M NaOH and ether. The organic phase was washed with water, dried and evaporated. The 20 residue was purified by RP-HPLC with acetonitrile and water containing 0.1% TFA as mobile phase. The appropriate fraction was evaporated and the residue extracted with 1M NaOH and ether. The subtitle compound was obtained from the organic phase as a colourless oil (400mg, 66%). 25 APCI-MS: m/z 361, 363 [MH*] iv) To a solution of compound (iii) (400mg, 1.1 mmol) in DCM (1 OmL) acetic anhydride (200pL, 2. 1mmol) was added and the mixture was left overnight. After evaporation the residue was dissolved in methanol and 1.5M sodiummethoxid in methanol (2mL) was 30 added. The mixture was left for 2h, evaporated and taken up in ether and water. A mixture WO 01/62728 PCT/SEO1/00403 132 of the two diastereomers was obtained from the organic phase. The diastereomers were separated by HPLC on a chiral column using a mixture of isohexane, 2-propanol and methanol as mobile phase. The isolated enantiomers were dissolved in methanol (1mL), acidified with 1M hydrochloric acid (lmL), diluted with water and lyophilized to give the 5 title compounds as white amorphous solids (156mg and 173mg). The absolute stereoisomerism was not assigned. APCI-MS: m/z 403, 405 [MH*] 10 Example 252 N-(5-Chloro-2-{3-[3-(4-chloro-benzyl)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl) acetamide trifluoroacetic acid salt i) 3-(4-Chloro-benzyl)-pyrrolidin-2-one is In a flask was added diisopropylamine (3.22 g, 31.8 mmole) and dry THF (60 ml). The content of the flask was kept under nitrogen, and was then cooled to.-76C. To the cool solution was dropwise added n-butyllithium (n-BuLi, 32 mmole, 20 ml, 1.6 M in hexane). After completed addition, the solution was stirred for 10 minutes, and a solution of 1 Trimethylsilanyl-pyrrolidin-2-one (5.00 g, 31.8 mmole, prepared according to literature 20 methods) in dry THF (5 ml) was added dropwise. The solution was then stirred for an additional 20 minutes and a solution of 4-Chlorobenzyl chloride (5.13 g, 32 mmole) in THF (5 ml) was added via a syringe during 5 minutes. The resulting mixture was stirred at -76'C for 1 hour, and was then allowed to reach the ambient temperature and was stirred over night. Water (40 ml) was added and the mixture was stirred vigorously for 60 25 minutes. The phases were separated and the organic phase was washed with brine, and was finally evaporated, giving an oil which crystallized on standing. The solid was triturated with heptane:EtOAc 2:1 and was filtered, giving a partly purified solid. The solid was purified on silica (DCM to DCM : MeOH 99:1 to 98:2 to 97:3 gradient) giving 1.3g (20%) of the sub-title compound. 30 WO 01/62728 PCT/SEO1/00403 133 'H-NMR (400 MHz, CDC1 3 ) 5: 7.27 (2H, d, J8.4Hz); 7.16 (2H, d, J8.4Hz); 5.43 (1H; bs): 3.31-3.13 (3H, m); 2.74-2.61 (2H, m); 2.20 -2.12 (1H, m); 1.88-1.77 (1H, m) ii) 3-(4-Chloro-benzyl)-pyrrolidine 5 In a flask was dissolved the compound obtained in a) (0.20 g, 0.95 molee, in dry THF (10 ml). LiAlH 4 (0.17 g, 4.53 mmole) was added in small portions over 10 minutes. After completed addition, the mixture was heated to 60'C for approximately 3h under nitrogen, and the reaction was monitored by LC-MS, and was quenched after completed reaction. Before quenching, the reaction was allowed to reach the ambient temperature, and water to (0.160 ml) was added cautiously drop by drop. NaOH (10% solution in water, 0.16 ml) was added dropwise, and finally another portion of water (0.48 ml). The mixture was stirred for 1 hour and was then filtered. The filtrate was concentrated in vaccuo giving the sub-title compound (0.18 g, 97%) as a colorless oil. is APCI-MS: m/z 196.1 [M+H] iii) N-(5-Chloro-2-{3-[3-(4-chloro-benzyl)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide trifluoroacetic acid salt The title compound was prepared according to the method described in Example 1 iii) from 20 the compound obtained in ii). 'H-NMR (400 MHz, DMSO) 6: 9.93-9.62 (1H, m); 9.12 (1H, s); 8.11 (1H, s); 7.38 (2H, d, J8.9 Hz); 7.29-7.23 (2H, m); 7.13-7.02 (2H, m); 6.11-6.02 (1H, m); 4.29-4.16 (1H, bs); 4.05-3.95 (1H, m); 3.95-3.87 (1H, m); 3.75-3.50 (2H, m); 3.40-3.22 (3H, m); 2.91-2.65 25 (3H, m); 2.62-2.52 (1H, m); 2.13 (3H, s); 2.11-1.94 (1H, m); 1.81-1.55 (1H, m) Example 253 N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrroidinyll-2-hydroxypropoxy}-4-methylphenyl)-1 pyrrolidinecarboxamide trifluoroacetate 30 WO 01/62728 PCT/SEO1/00403 134 i) 2-[(5-Methyl-2-nitrophenoxy)methylloxirane A mixture of 5-Methyl-2-nitrophenol (7.7g, 50mmol), potassium carbonate (13.8g, 0.1mmol) and epibromohydrine (8.25mL, 0.1mmol) was dissolved in DMF (1OOmL) and stirred 2-3 h at 100 C under an atmosphere of nitrogen. 5 The mixture was diluted with ether (0.5L) and extracted with water until pH=7. The organic phase was evaporated and the residue was purified by flash-chromatography on silica (DCM) to give the sub-title compound as a yellow solid (8.65g, 83%). 'H-NMR (400MHz, CDCl 3 ): S 7.80 (d,1H); 6.91 (s,1H); 6.86 (d,1H); 4.39 (dd,1H); 4.15 10 (dd,1H); 3.43-3.37 (m, 1H); 2.93 (dd,lH); 2.89 (dd,1H); 2.42 (s,3H) ii) 1-[3-(4-Chlorophenoxy)-1-pyrrolidinyll-3-(5-methyl-2-nitrophenoxy)-2-propanol A mixture of compound i) (1.05g, 5.Ommol) and 3-(4-chlorophenoxy)pyrrolidine (988mg, 5.0mmol) in ethanol (12mL) was refluxed for 2h. The solvent was evaporated to give the 15 crude product as an orange oil, which was used without further purification. APCI-MS: m/z 407, 409 [MH*] iii) 1-(2-Amino-5-methylphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol 20 To a stirred solution of compound ii) (2.1 g, 5.Ommol) in ethanol (1 OmL) tin(II) chloride dihydrate (5.6g, 25mmol) in 35% hydrochloric acid (6mL) was added at 50*C. An exothermic reaction started and the temperature increased rapidly to 75*C. The mixture was maintained at 60*C for 0.5h. The cooled mixture was alkalized with 1M sodium hydroxide (1 80mL) and extracted with ether, the organic phase washed with water, 25 dried and evaporated to give the subtitle compound as a pale yellow oil (1.34g, 7 1%). NMR: Due to a mixture of two diastereomeric pairs integration will result in parts of protons. 'H-NMR (400MHz, CDCl 3 ): 5 7.23 (d, 2H); 6.77 (d, 2H); 6.67-6.65 (m, 1H); WO 01/62728 PCT/SEO1/00403 135 6.64-6.63 (in, 1H); 4.83-4.76 (in, IH); 4.14-4.06 (in, iH); 4.01 (d, 2H); 3.71 (bs, 2H);~3.41 (bs, IH); 3.10 (dd, 0.5H); 3.01-2.90 (m, 1.75H); 2.87-2.70 (in, 2.7H); 2.66-2.57 (in, 1.5H); 2.28 (h, 1H); 2.25 (s, 3H); 2.06-1.95 (in, 1H) 5 APCI-MS: 377, 379 [MH*] iv) N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxypropoxy}-4 methylphenyl)-1-pyrrolidinecarboxamide trifluoroacetate A solution of compound (iii) (75mg, 0.2mmol) and di(tert-butyl) tricarbonate (53mg, 10 0.2mmol) in DCM (3mL) was stirred for lh at ambient temperature. Pyrrolidine (33IL, 0.4mmol) was added and the stirring continued for lh. The reaction was complete as determined by LCMS. TFA (1mL) was added and the solution was left for lh. The volatile parts were evaporated and the crude product purified by preparative RP-HPLC using acetonitrile and water containing 0.1% TFA as mobile phase. The appropriate fraction was 15 concentrated in vacuo and the residue lyophilized to give the title compound as a white amorphous solid (85mg, 72%). NMR: Due to a mixture of two diastereomeric pairs integration will result in parts of protons. Data are from the free base. 20 1 H-NMR (400MHz, CDC1 3 ): 8 8.03 (dd, 1H); 7.24 (d, 2H); 6.94 (bs, IH); 6.82-6.74 (in, 2H); 6.78 (d, 2H); 6.73-6.68 (in, 1H); 4.85-4.76 (in, iH); 4.11-3.94 (in, 3H); 3.52-3.42 (in, 5.6H); 3.11 (dd, 0.5H); 3.05-2.92 (in, 0.45H); 2.95 (d, iH); 2.87-2.72 (in, 2.5H); 2.62-2.52 (in, 1.4H); 2.37-2.21 (in, 0.7H); 2.29 (s, 3H); 2.08-1.90(m, 4.6H) 25 APCI-MS: m/z 474, 476 [MH*] Example 254 N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4 30 hydroxyphenyl)acetamide trifluoroacetate WO 01/62728 PCT/SEO1/00403 136 To a stirred solution of the free base of compound Example 265 iii) following (128mg, 0.29mmol) in DCM (4mL) under N, 1M boron tribromide in DCM (0.58mL, 0.58mmol) was added at ambient temperature. The heterogeneous mixture was stirred overnight and 5 poured into methanol. After evaporation the crude product was purified by RP-HPLC using acetonitrile and water containing 0.1% TFA as mobile phase. The appropriate fraction was lyophilized to give the title compound as a white amorphous solid (113mg, 73%). APCI-MS: m/z 421, 423 [MH*] 10 Example 255 N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyll-2-hydroxypropyl}oxy)-4 fluorophenyl]acetamide trifluoroacetic acid salt 15 i) (2S)-2-[(5- Fluoro-2-nitrophenoxy)methylloxirane In a flask was added (R)-glycidol (0.994 g, 13.4 mmole) and triphenylphosphine (3.52 g, 13.4 mmole) and THF (20 ml, dried over molecular sieves), and 5-fluoro-2-nitrophenol (2.10 g, 13.4 mmole). The mixture was stirred until a homogeneous solution was obtained. The solution was cooled in an ice bath and diethylazodicarboxylate (DEAD, 2.11 ml, 13.4 20 mmole) was added dropwise over a few minutes. After completed addition, the flask was allowed to reach room temperature and stirred for an additional 2 hours. The solvent was removed in vaccuo and to the residue was added chloroform (5-10 ml). The precipitate (PPh 3 O) was removed by filtration and the solid was washed with an additional amount of chloroform (5-10 ml). The filtrate was added to a flash column (SiO 2 , Heptane:Ethyl 25 acetate 4:1), and purified to give 2.02 g (71%) of the sub-title compound as a crystalline material after concentration of pure fractions. 'H-NMR (400 MHz, CDC1 3 ) 6: 7.97 (1H, dd, J9.3, 6.0 Hz); 6.86 (1H, dd, J 10.0, 2.5 Hz); 6.80-6.74 (1H, m); 4.44 (1H, dd, J11.4, 2.6 Hz); 4.12 (lH, dd, J11.2, 5.1 Hz); 3.44-3.38 30 (1H, m); 2.95 (1H, t, J4.5 Hz); 2.90 (1H, dd, J4.8, 2.6) WO 01/62728 PCT/SEO1/00403 137 ii) (2S)-1-[4-(3,4-Dichlorophenoxy)-1-piperidinyll-3-(5-fluoro-2-nitrophenoxy)-2 propanol In a vial was added 4-(3,4-dichlorophenoxy)-piperidine (0.123 g, 0.5 mmole) and the 5 compound obtained in i) (0.106 g, 0,5 mmole) and ethanol (99.5%, 3 ml). The vial was sealed and the content was heated with stirring at 65'C for 3 hours, and the reaction was monitored on LC-MS. The vial was allowed to cool and the solvent was evaporated, giving an oil, which was purified on silica (DCM to DCM:MeOH 99:1 to 98:2 to 97:3 as a stepwise gradient). Evaporation of pure fractions gave 0.22 g (96%) of the sub-title 10 compound as an oil. APCI-MS (m/z): 459.1 [M+H] iii) N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyll-2-hydroxypropyl} oxy)-4 15 fluorophenyllacetamide trifluoroacetic acid salt The compound obtained in ii) (0.22 g, 0.48 mmole) was dissolved in ethanol (99.5%, 7 ml) and heated with stirring to 60"C. A solution of SnCl 2 x 2H 2 0 (0.56 g , 5 equivalents) in concentrated hydrochloric acid (0.63 ml) was added and was stirred at 60'C for 1 hour. The mixture was then allowed to cool. The solution was alkalized by the addition of excess 2M 20 NaOH, and the solution was extracted with diethyl ether (3 x 50 ml). The combined ethereal solutions were washed with brine an evaporated. The obtained oil was dissolved in THF (8 ml), and water (8 ml) was added, followed by the addition of acetic anhydride (5001, 0.52 mmole). The mixture was stirred at 40'C for 15 minutes. The organic solvent was removed in vaccuo, and the residue was extracted with EtOAc (3 x 30 ml). The 25 combined organic phases were washed with brine and were then concentrated in vaccuo. The residual oil was purified on preparative HPLC giving 55g (20%, 98% purity) of the title compound as the trifluoro acetate, and as a white solid after lyophilization of pure fractions. 30 APCI-MS (m/z): 471.0, 472.0, 473.0 and 474.0 [M+H] WO 01/62728 PCT/SEO1/00403 138 Example 256 N-(2-(3-(4-Chloro-phenoxy)-pyrrolidin-1-yl)-2-hydroxy-propoxy)-4,6-difluoro phenyl)-acetamide hydrochloride 5 i) 3,5-Difluoro-6-nitrophenol To a stirred solution of 2,3,4-trifluoronitrobenzene (5g, 28.23mmol) in dry methanol (70ml) was added a solution of sodium (0.68, 29.46) in dry methanol (30ml). The solution was stirred until all starting material was consumed (-2h). After concentration water was 10 added and the solution was extracted with ether, dried over Na 2
SO
4 , filtered and concentrated to a yellow residue (4.65g). To the solution of the yellow residue in dichloromethane (140ml) was added boron tribromide (lM in dichloromethane, 40ml) and stirred at room temperature overnight. Water was then added and the solution stirred for further 30 min. The organic phase was separated and the water phase was extracted with is ether. The combined organic phase were dried over Na 2
SO
4 , filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and neutralized with 6M HCl and extracted with ether, dried over Na2SO 4 and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with 20 EtOAc:Heptan; 1:2 as eluent to give the desired product 2g, 11.42mmol. GC-MS: m/z 175(M+) 'HNMR (400MHz, CD 3 0D) 8ppm, 6.63-6.68(1H, m), 6.60-6.67(1H, dt) 25 ii) 2-{(3,5-Difluoro-2-nitrophenoxy)methylloxirane To a mixture of 3,5-diflluoro-6-nitrophenol (100mg, 0.571mmol) and potassium carbonate (394mg) in DMF (5ml) was added epibromohydrin (80mg, 0.582mmol) and was stirred at 70*C for 3hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by chromatography (ethyl acetate: heptan 30 1:3) to give the desired product as a solid 161mg (0.696mmol).
WO 01/62728 PCT/SEO1/00403 139 GC-MS: m/z 231 (M+) iii) 1-[3-(4-Chlorophenoxy)-1-pyrrolidinyll-3-(3,5-difluoro-2-nitrophenoxy)-2 5 propanol A solution of 3-(4-chlorophenoxy)pyrrolidine and 2-[(3,5-difluoro-2 nitrophenoxy)methyl]oxirane (50mg, 0.216mmol) in ethanol was refluxed for 3hrs. The solvent was distilled off under reduced pressure and the resulting residue purified by silica gel column chromatography (dichloromethane/methanol 20:1) to give 45mg (0.1 05mmol) 10 of the title compound as solid. iv) N-(2-(3-(4-Chloro-phenoxy)-pyrrolidin-1-yl)-2-hydroxy-propoxy)-4,6-difluoro phenyl)-acetamide hydrochloride Platinum oxide on carbon was added to a solution of 1-[3-(4-chlorophenoxy)-1.
15 pyrrolidinyl]-3-(3,5-difluoro-2-nitrophenoxy)-2-propanol (40mg, 0.0932mmol) in ethanol and the mixture was hydrogenated for 4hrs at 1 atm. The mixture was filtered through Celite and washed several times with warm ethanol and the combined filtrate were concentrated in vacuo. To the resulting yellow residue was taken up in dichloromethane and acetic anhydride was added to the solution. The solution was stirred at room 20 temperature for 2hrs then concentrated. Addition of 1.OM ethereal hydrogen chloride solution gave the title product as solid 20mg APCI-MS: m/z 441[MH*] 25 Example 257 N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyll-2 hydroxypropyl}oxy)-4-fluorophenyllacetamide trifluoroacetic acid salt The title compound was prepared according to the procedure described in Example 260 30 following.
WO 01/62728 PCT/SEO1/00403 140 'H-NMR (400 MHz, DMSO-d6) 8: 9.89 (1H, bs); 9.05 (1H, s); 7.79 (1H, dd, J8.8, 6.6 Hz); 7.37 (2H, d, J9.6 Hz); 7.00-6.94 (3H, m); 6.75 (1H, dt, J8.6, 2.6 Hz); 6.00 (1H, bs); 5.17-5.10 (1H, m); 4.32-4.20 (1H, m); 4.05 (1H, dd, J10.1, 4.6 Hz); 3.97 (1H, dd, J9.9, 5 5.7 Hz); 3.78-3.50 (3H, m); 3.47 (1H, t, J 11.6 Hz); 3.17 (1H, t, J 13.3 Hz); 2.83 (1H, p, J 6.9 Hz); 2.07 (3H, s); 1.90-1.80 (1 H, m); 1.42 (3H, d, J6.4 Hz) Example 258 N-[2-({(2S)-3-[(3R)-3-(4-Chlorobenzyl)pyrrolidinyll-2 10 hydroxypropylloxy)phenyllacetamide hydrochloride Prepared by the method described in Example 251. Example 259 15 N-{2-[(2R)- (3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrroidinyl}-2-hydroxypropyl)oxy] 4-fluorophenyl}acetamide APCI-MS: m/z 423.1 [M+] 20 Example 260 N-[2-({(2S)-3-[(2R,4S)-4-(4-chlorophenoxy)-2-methylpyrrolidinyl-2 hydroxypropyl}oxy) phenylacetamide trifluoroacetic acid salt i) 1-(tert-Butyl) 2-methyl (2S, 4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate 25 In a flask was dissolved (2S,4R)-4-Hydroxy-proline hydrochloride (5.4 g, 30 mmole) in a mixture of THF (200 ml), water (170 ml) and NaOH (30 ml, 2 M in water, 60 molee. To this emulsion was added di-tert-butyldicarbonate (Boc 2 O, 6.54 g, 30 mmole), and the mixture was stirred vigorously for 1 hour. Ether (100 ml) was added and the phases were allowed to separate. The aqueous phase was extracted with an additional 100 ml of ether. 30 The aqueous phase was discarded and the combined organic phases were washed with IM WO 01/62728 PCT/SEO1/00403 141 HCI (aq.) and potassium carbonate (saturated, aq.) and brine. The extract was dried with Na 2
SO
4 and was concentrated in vaccuo to give a residue, which was purified on silica (Heptane:EtOAc 5:1 to 3:1 to 1:1 stepwise gradient, spots visualized with 1 2 /MeOH). Evaporation of pure fractions were concentrated in vaccuo to give 4.2 g (57%) of the sub 5 title compound as a colorless oil. 'H-NMR (400 MHz, CDCl 3 ) 6: 4.50 (1H, bs); 4.45-4.35 (1H, in); 3.74 (3H, s); 3.64 (1H, dd, J 11.7, 4.3 Hz); 3.59-3.42 (1H, m); 2.35-2.20 (1H, m); 2.14-2.03 (lH, m); 1.97 (1H, dd, J23.3, 3.7 Hz); 1.44 (9H, d, J 18.9 Hz) 10 ii) 1-(tert-Butyl) 2-methyl (2S, 4S)-4-(4-chlorophenoxy)-1,2 pyrrolidinedicarboxylate In a flask was dissolved the compound obtained in i) (2.54 g, 10.3 mmole), triphenylphosphine (2.71 g, 10.3 mmole) and 4-Chlorophenol (1.33 g, 10.3 mmole) in THF (50 ml, dried over molecular sieves) under magnetic stirring. The flask was cooled in an ice is bath and, to this stirred solution was added diethylazodicarboxylate (DEAD, 1.8 g, 10.3 mmole) dropwise under a few minutes. The reaction was allowed to stand over night, allowing the ice to melt and the reaction to reach room temperature. The solvents were evaporated and the residue was treated with ether (30 ml), allowing the phosphine oxide to precipitate. The solid was removed by filtration and the filtrate concentrated in vaccuo. The 20 residue was purified on silica (Heptane:EtOAc 8:1 to 6:1 to 3:1, stepwise gradient. Spots on TLC were visualized by Seebach's reagent). Concentration of pure fractions gave 2.51 g (68%) of the sub-title compound as a colorless viscous oil. 'H-NMR (400 MHz, CDC1 3 ) 6: 7.26-7.20 (2H, m); 6.77-6.70 (2H, in); 4.86 (1H. bs); 4.55 25 (1/2 H, dd, J8.6, 2.6 Hz); 4.43 (1/2 H, dd, J7.6, 3.9 Hz); 3.84-3.60 (5H, m); 2.53-2.36 (2H, m); 1.47 (9H, d, J 18.2 Hz) iii) tert-Butyl (2S,4S)-4-(4-chlorophenoxy)-2-(hydroxymethyl)-1 pyrrolidinecarboxylate WO 01/62728 PCT/SEO1/00403 142 In a flask was dissolved the compound obtained in ii) (0.951 g, 2.67 mmole) in THF (10 ml, dried over sieves). The solution was cooled in an ice bath and LiBH 4 (0.09 g, 4.07 mmole) was added. The mixture was stirred over night, allowing the ice to cool, and the solution to reach room temperature. The crude mixture was then partitioned between 5 EtOAc (100 ml) and water (100 ml). The aqueous phase was discarded and the organic solution was washed with 0.5M HCl (aq.), NaHCO 3 (sat, aq) and brine. The solution was evaporated to give an oil which seem to be contaminated with inorganic salts. Dissolution in DCM and filtration through Celite@ afforded 0.82 g (94%) of the sub-title compound as a colorless oil. 10 'H-NMR (400 MHz, DMSO-d6) 5: 7.33 (2H, d, J9.5 Hz); 6.95 (2H, d, J9.5); 4.96 (lH, bs); 4.71 (1H, bs); 3.84-3.55 (3H, in); 3.32 (2H, bs); 2.29-2.07 (2H, in); 1.41 (9H, s) iv) tert-Butyl (2S,4S)-4-(4-chlorophenoxy)-2-{[(methylsulfonyl)oxymethyl}-1 is pyrrolidine carboxylate In a flask was dissolved the compound obtained in iii) (0.82 g, 2.5 mmole) in dichloromethane (10 ml, dried over molecular sieves). The flask was cooled on ice, and triethylamine (0.69 ml, 5.0 mole) was added from a syringe. Methanesulfonylchloride (0.30 ml, 3.86 mmole) was added dropwise over a few minutes, and the obtained mixture 20 was stirred over night, allowing the ice to melt. To the mixture was added DCM (60 ml), and the solution was washed with 1M HC1 (aq), NaHCO 3 (sat, aq), and brine. The solution was evaporated giving 0.876 g (86%) of the sub-title compound as a yellow oil, which was used in the next step without any further purification. 25 'H-NMR (400 MHz, DMSO-d6) 8: 7.35 (2H, d, J9.4 Hz); 6.99 (2H, d, J9.4 Hz); 5.07 5.01 (lH, m); 4.37 (lH, dd, J8.9, 4.2 Hz); 4.20-4.05 (2H, in); 3.71 (lH, dd, J 11.8, 5.0 Hz); 3.32 (2H, s); 3.15 (3H, s); 2.07 (lH, d, J 14.4 Hz); 1.41 (9H, s) v) tert-Butyl (2R,4S)-4-(4-chlorophenoxy)-2-methyl-1-pyrrolidinecarboxylate WO 01/62728 PCT/SEO1/00403 143 In a flask was dissolved the compound obtained in iv) (0.876 g, 2.16 mmole) in THF (10 ml, dried over molecular sieves). The reaction mixture was kept under an inert atmosphere and was then cooled in an ice bath. LiB(Et) 3 H (IM Lithium triethylborohydride in THF, 9 ml, 9 mmole) was added with a syringe over 15 minutes. The ice bath was removed and the 5 mixture was stirred over night. The crude mixture was partitioned between EtOAc (100 ml) and water (100 ml). The aqueous phase was removed, and the organic phase was washed with IM HC1 (aq.), NaHCO 3 (sat, aq), and brine. The solution was evaporated and the residue was purified on silica (Heptane:EtOAc 10:1 to 5:1 to 4:1 to 2:1 gradient. TLC spots were visualized by Seebach's reagent), giving 0.401 g (60%) of the sub-title compound as 10 a colorless oil. 'H-NMR (400 MHz, DMSO-d6) 5: 7.33 (2H, d, J8.7 Hz); 6.96 (2H, d, J8.7 Hz); 5.00 4.94 (1H, m); 3.89 (1H, bs); 3.64 (1H, dd, J 12.5, 5.2 Hz); 3.38 (1H, d, J 12.2 Hz); 2.41 2.28 (1H, m); 1.79 (1H, d, J 13.7 Hz); 1.40 (9H, s); 1.23 (3H, d, J6.6 Hz) 15 vi) (2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidine trifluoroacetic acid salt In a flask was dissolved the compound obtained in v) (0.390 g, 1.25 mmole) in dichloromethane (DCM, 15 ml). To this solution was added TFA (trifluoroacetic acid, 6 ml) and the mixture was allowed to stand for 3 hours, after which the volatiles were 20 removed in vaccuo. The residue was co-evaporated twice with DCM, giving the sub-title compound as an oil. APCI-MS (m/z): 212 [M+H] 25 vii) N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl-2 hydroxypropyl}oxy) phenylacetamide trifluoroacetic acid salt The title compound was prepared according to the method outlined in Example 255 starting from the material obtained in vi) and (2S)-2-[(2-nitrophenoxy)methyl]oxirane. The compound was obtained in 25% yield. 30 WO 01/62728 PCT/SEO1/00403 144 'H-NMR (400 MHz, DMSO-d 6 ) 6: 9.88 (1H, bs); 9.02 (IH, s); 7.89 (1H, d. J7.7 Hz); 7.37 (2H, d, J7.7 Hz); 7.09-6.88 (5H, m); 6.02 (1H, bs); 5.18-5.11 (1H, m); 4.34-4.22 (IH, m); 4.02 (1H, dd, J10.2, 4.3 Hz); 3.94 (1H, dd, J9.8, 5.7 Hz); 3.77-3.30 (4H, m): 3.19 (1H, t, J 10.7 Hz); 2.84 (IH, p, J6.7 Hz); 2.09 (3H, s); 1.91-1.81 (IH, m); 1.43 (3H. d. J6.4 Hz) 5 APCI-MS (m/z): 419.2 [M+H] Example 261 N-{2-1(2S)-(3-{(3R)-3-{(4-Chlorophenyl)oxyl-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4 10 fluorophenyllacetamide APCI-MS: m/z 423.1 [M+] Example 262 15 N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxypropoxy}-4-methylphenyl) N,N-dimethylurea trifluoroacetate The title compound was prepared by analogy to the methods described in Example 253 starting from compound iii) (75mg, 0.2mmol) and dimethylamine (2M in THF, 200pL, 20 0.4mmol). The substance was obtained as a white amorphous solid (73mg, 65%). 'H-NMR (400MHz, MeOH-d4): 6 7.54 (dd, 1H); 7.51 (d, 2H); 7.16 and 7.15 (d, 2H); 7.05 (bs, 1H); 6.96 (bd, 1H); 5.40-5.35 (m, 1H); 4.54-4.46 (m, 1H); 4.27 (d, 2H); 4.16-3.56 (m, 6H); 3.20 (bs, 6H); 2.84-2.59 (m, 1H); 2.59-2.44 (m, 1H); 2.50 (s,3H). 25 APCI-MS: m/z 448, 450 [MH*] Example 263 N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide 30 WO 01/62728 PCT/SEO1/00403 145 i) tert-Butyl-3-hydroxy-1-pyrrolidinecarboxylate To a solution of 3-hydroxy-1-pyrrolidine (871 mg, 10 mmol) in THF (30 mL) was added di-(tert.butyl) dicarbonate (2.18 g, 10 mmol) in THF (2 mL) and the reaction mixture kept on stirring at room temperature for overnight. The solvent was removed in vacuo and the 5 residue was purified by flash chromatography (0-2% MeOH in CHC 3 ) to give the subtitled compound (1.7g). 'H-NMR (CDC1 3 , 400 MHz): 5 4.45 (in, 1H); 3.55-3.25 (in, 4H); 2.18-1.85 (m, 3H); 1.45 (s, 9H). 10 APCI-MS: m/z 166 (M-Boc). ii) tert-Butyl-2-oxo-1-pyrrolidinecarboxylate Chromium (vi) oxide (800 mg, 8.0 mmol) was added to pyridine (1.6 mL) in CH 2 C1 2 (10 mL) and the resulting solution was stirred for 15 min at room temperature. A solution of 15 tert.butyl-3-hydroxy-l-pyrrolidinecarboxylate (374.5 mg, 2.0 mmol) in CHCl 2 (5 mL) was added, immediately followed by acetic anhydride and the reaction mixture kept at room temperature for 15 min. After addition of ethyl acetate, decanted and filtered through a short column of silica gel. The filtrate was concentrated to give the subtitled product (193 mg) and was used directly in the next step. 20 ii) tert-Butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate Tert.butyl-2-oxo-1-pyrrolidinecarboxylate (190 mg, 1.02 mmol), 4-chloroaniline (64 mg, 0.5 mmol) and acetic acid (184 mg) were mixed in dichloroethane (5 mL). Sodium triacetoxyborohydride (326.5 mg) was added and the reaction mixture kept on stirring at 25 room temperature for overnight. After addition of aq. NaHCO 3 the reaction mixture was diluted by addition of ethyl acetate. Two layers were separated. The organic layer was dried over Na 2
SO
4 , filtered, concentrated. The residue was purified by flash chromatography (0-15% ethyl acetate in petroleum spirit, 40-60) to give the subtitled product (140 mg). 30 WO 01/62728 PCT/SEO1/00403 146 'H-NMR (CDCl 3 , 400 MHz): 6 7.18 (in, 2H); 6.50 (in, 2H); 3.99 (in, 1H); 3.70 (in, 2Ii); 3.46 (in, 2H); 3.20 (in, 1H); 2.18 (in, 1H); 1.87 (in, 1H); 1.45 (s, 9H). APCI-MS: m/z 197 (M-Boc). 5 iv) N-(4-Chlorophenyl)-3-pyrrolidinamine (2xCF 3 COOH) To a solution of tert.butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate (130 mg, 0.438 mmol) in CH 2 C1 2 (5 mL) was added CF 3 COOH (1 mL). After 30 min the volatiles were removed in vacuo to give the subtitled product (186 ing) and was used directly in the next step. 10 y) N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyll-2-hydroxypropoxy}phenyl)acetamide A mixture of N-(4-chlorophenyl)-3-pyrrolidinamine (2xCF 3 COOH), (186 mg, 0.438 . mmol), N-[2-(2-oxiranylmethoxy)phenyl]acetamide (91 mg, 0.438 mmol) and K 2 C0 3 (200 mg) in ethanol (6 mL) was kept on stirring at 65 'C for 2.5 h. The volatiles were removed 15 in vacuo. The residue was partitioned between ethyl acetate and aq. NH 4 C1 solution. The organic layer was washed with water, dried over Na 2
SO
4 , filtered and concentrated. The residue was purified by flash chromatography (0-3% MeOH in CHC1 3 ) to give the titled product (70 mg). 20 'H-NMR (CDC1 3 , 400 MHz): 6 8.35 (m, 1H); 8.21 (br.s, 1H); 7.12 (in, 2H); 7.01 (in, 2H); 6.92 (in, 1H); 6.48 (m, 2H); 4.13-3.92 (m, 4H); 3.84 (br. s, 1H); 2.99 (in, 1H); 2.87-2.30 (in, 6H); 2.18 (s, 3H); 1.66 (in, 1H). APCI-MS: m/z 446 (MH). 25 Example 264 N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1 methylpropyl)oxy]phenyl}acetamide hydrochloride 30 i) N-{2-[(1-Methyl-2-propenyl)oxyphenyl}acetamide WO 01/62728 PCT/SEO1/00403 147 The compound (557 mg, 40%) was prepared from 3-chloro-1-butene (747 ml, 7.42 mrhol) and 2-acetamidophenol (1.02 g, 6.75 mmol) analogously to that described in Example 8 i). 1 H-NMR (400 MHz, CDC1 3 ): 5 8.37 (m, 1H), 7.80 (bs, 1H), 6.94 (m, 3H). 5.93 (m, 1H), 5 5.25 (m, 2H), 4.84 (m, IH), 2.21 (s, 3H), 1.49 (d, J6.3 Hz, 3H). ii) N-{2-[1-(2-Oxiranyl)ethoxylphenyl}acetamide The compound was prepared from N- {2-[(1 -Methyl-2-propenyl)oxy]phenyl } acetamide (549 mg, 2.67 mmol) and m-chloroperbenzoic acid (80 %, 923 mg, 4.28 mmol) to analogously to that described in Example 8 (ii). Purification was done on silica gel with petroleum ether/ethyl acetate 10/15 as eluent. This gave separation of the two diastereomeric pairs. Diastereomer 1: (53 mg, 9%), Rf=0.27 15 Diastereomer 2: (406 mg, 69 %), Rf=0.20 1 H-NMR (400 MHz, CDC1 3 ): 8 8.39 (m, 1H), 8.01 (bs, 1H), 7.00 (m, 3H), 3.98 (m, 1H), 3.24 (m, 1H), 2.94 (t, J4.5 Hz, 1H), 2.71 (dd, J2.6 Hz, J4.5 Hz, I H), 2.23 (s, 3H), 1.47 (d, J6.3 Hz, 3 H). 20 iii) N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1 methylpropyl)oxylphenyl}acetamide hydrochloride The title compound (230 mg, 100 %) was prepared from N-[2-(1 oxiranylethoxy)phenyl]acetainide diasteromer 2 (123 mg, 0.557 mmol) and 3-(4 25 chlorophenoxy)pyrrolidine (100 mg, 0.506 mmol) analogously to that described in Example 1 (iii). 1 H-NMR (400 MHz, MeOD): 8 7.86 (m, 1H), 7.30 (m, 2H), 7.09 (m, 2H), 6.97 (m, 3H), 5,21 (m, 1H), 4,51 (m, 1H), 3.83-4.22 (m, 3H), 3.37-3.62 (m, 4H), 2.68 (m, %/ H), 2.38 (m, 30 1H), 2.27 (m, 2 H), 2.19 (m, 3H), 1.32 (m, 3H).
WO 01/62728 PCT/SEO1/00403 148 MS-APCI+: m/z 419 [MH*] Example 265 N-(2-{3-{3-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxypropoxy}-4 5 methoxyphenyl)acetamide hydrochloride i) 1-{3-(4-Chlorophenoxy)-1-pyrrolidinyll-3-(5-methoxy-2-nitrophenoxy)-2-propanol The subtitle compound was prepared in analogy of Example 253 ii) from 2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (320mg, 1.6mmol) and 1o 3-(4-chlorophenoxy)pyrrolidine (365mg, 1.6mmol). The crude product was obtained.as a yellow oil (580mg) and was used without further purification. APCI-MS: m/z 423, 425 [MH*] 1s ii) 1-(2-Amino-5-methoxyphenoxy)-3-{3-(4-chlorophenoxy)-1-pyrrolidiny1]-2 propanol The subtitle compound was prepared in analogy of Example 253 iii) from compound i) (290mg, 0.7mmol). The crude compound was obtained as a colourless oil (233mg, 85%) and was used without further purification. 20 APCI-MS: m/z 393, 395 [MH] iii) N-(2-{3-{3-(4-Chlorophenoxy)-1-pyrrolidinyll-2-hydroxypropoxy}-4 methoxyphenyl)acetamide hydrochloride 25 To a solution of compound (ii) (157mg, 0.4mmol) in pyridine (3mL) acetic anhydride (lmL) was added. The mixture was stirred for 1 h at ambient temperature. After evaporation the residue was dissolved in methanol (mL) and 1.5M sodium methoxide in methanol (lmL) was added. The mixture was left overnight at ambient temperature. After evaporation the residue was taken up in ether and water. The free base of the title 30 compound was obtained from the organic phase as a colourless oil (17 1mg, 98%). The free WO 01/62728 PCT/SEO1/00403 149 base (43mg) was dissolved in methanol (5mL), acidified with IM hydrochloric acid till pH<2, diluted with water (50mL) and lyophilized. The title compound was obtained as a white amorphous solid (30mg, 64%). 5 APCI-MS: m/z 435, 437 [MH*] Example 266 N-(2-[3-(4-Chloro-benzyloxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl)-acetamide trifluoroacetic acid salt. 10 i) 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 3-hydroxy-1-pyrrolidinecarboxylic acid (0.27 g, 1.44 mmol) in dry THF (4 mL) was added dropwise to a cold (0 C), stirred suspension of sodium hydride (0.078 g, 2.17 mmol, ca. 50% suspension in oil) in THF (10 mL). After 30 min. a solution is of 4-chlororbenzyl bromide (0.36 g, 1.74 mmol) in THF (2 mL) was added and the resulting suspension was stirred at R.T. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with saturated aqueous sodium chloride, dried and concentrated. The residue was subjected to flash chromatography (heptane-ethyl acetate, 20 6:1) to afford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrrolidine-I-carboxylic acid tert-butyl ester as an oil (0.30 g, 66.8%). 'H-NMR (CDCl 3 ): 6 7.30 (m, 4H), 4.49 (bs, 2H), 4.11 (in, 1H), 3.45 (m, 4H), 1.90-2.08 (m, 2H), 1.46 (s, 9H). 25 ii) 3-(4-Chloro-benzyloxy)-pyrrolidine A solution of 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.9 mmol) in aqueous 90% formic acid (7.5 mL) was stirred at (00 C) for 30 min. then at room temperature overnight. The solvents were removed under reduced pressure and the 30 residue was treated with saturated aqueous potassium carbonate and extracted twice with n- WO 01/62728 PCT/SEO1/00403 150 butanol. The combined organic extracts was concentrated and the residue was purified by flash chromatography (SiO 2 , dichloromethane-methanol-ammonium hydroxide, 8:8:1 then 50:10:1) to afford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrrolidine (0.13 g, 70%). 5 'H-NMR (DMSO-d 6 ): 8 7.32-7.41 (m, 4H), 4.42 (s, 2H), 4.02 (m, IH), 3.18 (bs, 3H), 2.75 2.86 (m, 3H), 2.68 (m, 1H), 1.66-1.81 (m, 2H). APCI-MS: m/z 212 [MH*]. 10 iii) N-(2-{3-(4-Chloro-benzyloxy)-pyrrolidin-1-yll-2-hydroxy-propoxy)-phenyl) acetamide trifluoroacetic acid salt A solution of 3-(4-chloro-benzyloxy)-pyrrolidine (0.050 g, 0.24 mmol) and N-(2 oxiranylmethoxy-phenyl)-acetamide (0.049 g, 0.24 mmol) in absolute ethanol (3 mL) was is heated in a closed vial at 700 C for 2h. The product was purified by HPLC to afford the title compound (0.60 g, 47%). 'H-NMR (CD 3 0D): 5 7.85 (m, 1H), 7.35 (m, 4H), 7.12 (m, 1H), 7.02 (d, 1H, J= 8 Hz), 6.96 (m, 1H), 4.56 (m, 2H), 4.39 (m, 2H), 4.05 (d, 2H, J = 5.9 Hz), 3.85 (m, 2h), 3.48 (m, 20 4H), 2.10-2.55 (m, 5H). APCI-MS: m/z 419 [MH*] and 421 [MH+2*]. Example 267 25 N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yll-2-hydroxy-2-methyl-propoxy} phenyl)-acetamide The compound was prepared by a method analogous to that of Example 270 following. 30 APCI-MS: m/z 419 [MH*] WO 01/62728 PCT/SEO1/00403 151 Example 268 N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy}-5-chloro-phenyl)-acetamide (diastereomeric mixture) 5 Was prepared by analogy to Example 271 following from N-{5-chloro-2-[(lR,2S,5R)*-6 oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide (5.3 mg, 20 pLmol) and (3S)-3-(3,4 difluoro-phenoxy)-pyrrolidine (4.0 mg, 20 tmol). 10 MS-APCI+: m/z 467 [M+]. Example 269 N-[2-({(2R,3S) *-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxybutylloxy)-4 methylphenyllacetamide (diastereomeric mixture) 15 Was prepared analogies to Example 271 following from N-(4-methyl-2-{[(2S,3R)*-3 methyloxiranyl]methoxy}phenyl)acetamide (4.7 mg, 20 pmol) and (3S)-3-(4-Chloro phenoxy)-pyrrolidine (4.0 mg, 20 mol). 20 MS-APCI+: m/z 433 [M+]. Example 270 N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy] 4-fluorophenyl}acetamide hydrochloride 25 i) N-[4-Fluoro-2-(2-methyl-allyloxy)-phenyll-acetamide 3-Chloro-2-methylpropene (1.36g, 15 mmol) was added to a mixture of 5-fluoro-2-nitro phenol (1.57 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol), tetrabutylammonium hydrogen sulfate (0.068 g, 0.2 mmol) and acetonitrile (30 ml), and the mixture was heated 30 under reflux for 18 h. The cold reaction mixture was diluted with toluene and washed with WO 01/62728 PCT/SEO1/00403 152 5 % aqueous potassium carbonate, dried and evaporated. A part of the residue (0.631 g, 3 mmol), sodium dithionite (1.04 g, 6 mmol) in EtOH-THF-H 2 0 (2:1:1, 3 ml) was heated at 75 "C for 4 h. The mixture was portioned between dichloromethane and 15 % aqueous potassium carbonate and the organic solution dried and concentrated. The obtained residue 5 was diluted with methanol (1.5 ml) and reacted with acetic anhydride (1.5 ml) at 50 "C for 2 min and allowed to attend room temperature during 20 min, then pyridine (4 ml) was added and the solution heated again at 50 C for 3 min, cold and concentrated. The material was purified by silica gel chromatography (light petroleum-ethyl acetate 2:1) to give 95 mg of the subtitle compound. 10 .H-NMR (300MHz, CDC1 3 ): 6 8.28 (dd, 1H,), 7.62 (bs, IH), 6.70-6.60 (m, 2H), 5.07 (dd, 2H), 4.49 (s, 2H), 2.20 (s, 3H), 1.84 (s, 3H). ii) N-(4-Fluoro-2-{[(2-methyl-2-oxiranyl)methylloxy}phenyl)acetamide 15 The subtitle compound was prepared from N-[4-fluoro-2-(2-methyl-allyloxy)-phenyl] acetamide analogously as described in Example 8 ii). 'H-NMR (300MHz, CDCl 3 ): 6 8.31-8.26 (dd, 1H,), 7.79 (bs, 1H), 6.75-6.65 (m, 2H), 4.14 (d, 1H), 3.97 (d, IH), 2.93 (d, 1H), 2.80 (d, 1H), 2.21 (s, 3H), 1.50 (s, 3H). 20 APCI-MS: m/z 240 [MH*] iii) N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy] -1 -piperidinyl}-2-hydroxy-2 methylpropyl)oxyl-4-fluorophenyl}acetamide hydrochloride 25 A solution of 4-(3,4-dichloro-phenoxy)-piperidine (36 mg, 0.146 mmol), N-(4-fluoro-2 {[(2-methyl-2-oxiranyl)methyl]oxy}phenyl)acetamide (35 g, 0.146 mmol) in EtOH (1 ml, 95 %) was stirred for 2.5 hours at 77 "C in a sealed vial. The solvent was evaporated and the residue was purified on silica (dichloromethane-methanol, 15:1, containing 1% of
NH
4 0H (25%) to give 45 mg of the corresponding free amine of the title compound. 30 WO 01/62728 PCT/SEO1/00403 153 'H-NMR of the corresponding free amine of the title compound. (400MHz, CDC1 3 ): 8 8.26-8.22 (dd, 1H), 7.89 (bs, 1H), 7.31 (d, lH), 7.01 (d, 1H), 6.77 6.65 (m, 3H), 4.30 (m, 1H), 3.80 (dd, 2H), 2.93-2.81 (m, 2H), 2.67 (d, 1H), 2.63-2.51 (m, 2H), 2.45 (d, 1H), 2.19 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.62 (bs, 1H), 1.31 (s, 3H). 5 iv) N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxyl-1-piperidinyl}-2-hydroxy-2 methylpropyl)oxyl-4-fluorophenyl}acetamide hydrochloride A solution of the free amine in methanol (10 ml) was acidified with HCI (conc., 0.020 ml) to pH 3 and concentrated. The residue was coevaporated three times with toluene to give 10 the title hydrochloride compound as a white powder. APCI-MS: m/z 485, 487 [MH*] Example 271 15 N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-Chloro-phenoxy)-pyrroidin-1-yl]-2-hydroxy cyclopentyloxy}-4-fluoro-phenyl)-acetamide (diastereomeric mixture) N- {4-fluoro-2-[(1R,2S,5R)*-6-oxabicyclo[3.l.0]hex-2-yloxy]phenyl} acetamide (5.0 mg, 20 .mol) and (3S)-3-(4-Chloro-phenoxy)-pyrrolidine (3.9 mg, 20 tmol) were 20 dissolved in a 2M solution of LiCO 4 in acetonitrile (0.2 ml) and heated in a sealed tube to 100"C. Dilution by ethyl acetate, neutral aqueous workup and evaporation of the solvent gave a crude product which was used without further purification. MS-APCI+: m/z 449 [M+]. 25 Example 272 N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide 30 APCI-MS: m/z 441.1 [MH*] WO 01/62728 PCT/SEO1/00403 154 Example 273 N-(5-Chloro-2-{3-{3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide 5 APCI-MS: m/z 423.1 [MH*] Example 274 N-(4-Cyano-2-{3-{4-(3,4-dichloroanilino)-1-piperidinyll-2 10 hydroxypropoxy}phenyl)acetamide APCI-MS: m/z 477[MH*] Example 275 15 N-(4-Hydroxy-2-{(1S,2R,3S)*-3-{(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 hydroxy-cyclopentyloxy}-phenyl)-acetamide (diastereomeric mixture) i) N-{4-methoxy-2-[(1R,2S,5R)*-6-oxabicyclo[3. 1.0]hex-2-yloxy]phenyl} acetamide (32 mg, 122 ptmol) and (3S)-3-(4-Chloro-phenoxy)-pyrrolidine (24 mg, 122 ptmol) were 20 dissolved in a 2M solution of LiCIO 4 in acetonitrile (1 ml) and heated in a sealed tube to 100"C. Dilution by ethylacetate, neutral aqueous workup and evaporation of the solvents gave 62 mg (110%) of the crude addition product which was reacted with bortribromide (1M in CH 2 Cl 2 , 0.37 mL, 371 pmol) in dichloromethane (1 mL) at room temperature over night. The reaction was quenched with methanol (1.0 mL) and all volatile components 25 were evaporated. The remaining crude was subjected to a reversed phase HPLC giving 30 mg (54 %) of the title compound as a diastereomeric mixture. MS-APCI+: m/z 447.1 [MH+]. 30 ii) Separation of the diastereomers WO 01/62728 PCT/SEO1/00403 155 The above under i) described diastereomeric mixture was subjected to chiral phase HPLC (stationary phase: Chiralpak AD; mobile phase: iso-hexane/iso propanol/methanol/diethylamine = 80:16:4:0.1) with the compound of Example 276 as the 5 first and the compound of Example 277 as the second eluted stereoisomer. The assignment of the absolute configuration of the respective stereoisomer beneath is set by will and exchangeable. Example 276 10 N-(4-Hydroxy-2-{(1S,2R,3S)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide 'H-NMR (400MHz, CDC1 3 ; OH-protons are neglected): 8 8.02 (1H, s), 7.49 (1H, d, J 8.4Hz), 7.17 (2H, d, J 8.9Hz), 6.71 (2H, d, J 8.8Hz), 6.43 (1H, s), 6.34 (1H, d, J 7.2Hz), 15 4.76 (IH, m), 4.39 (1H, m), 4.09 (1H, m), 3.10-2.95 (3H, m), 2.89 (1H, m), 2.77 (1H, m), 2.24 (1H, m), 2.08 (3H, s), 2.10-1.84 (3H, m), 1.75 (1H, m), 1.59 (1H, m). MS-APCI+ : m/z 447.1 [MH+].
[C]
22 = + 49.5 (CH 2
C
2 ). 20 Example 277 N-(4-Hydroxy-2-{(1R,2S,3R)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 hydroxy-cyclopentyloxy}-phenyl)-acetamide 'H-NMR (400MHz, CDC1 3 ; OH-protons are neglected): 5 7.75 (1H, s), 7.60 (1H, d, J 25 8.4Hz), 7.19 (2H, d, J 8.3Hz), 6.73 (2H, d, J 8.6Hz), 6.57 (1H, s), 6.38 (1H, d, J 8.4Hz), 4.77(IH, m), 4.43 (1H, m), 4.21 (1H, m), 3.09-2.94 (3H, m), 2.79 (1H, m), 2.68 (lH, m), 2.28 (1H, m), 2.08 (3H, s), 2.05-1.90 (3H, m), 1.86 (1H, m), 1.53 (1H, m). MS-APCI+ : m/z 447.1 [MH+]. [a] 22 - 45.2 (CH 2
C
2
)
30 WO 01/62728 PCT/SEO1/00403 156 The diastereomers of Examples 278 and 279 were prepared by methods analogous to those used to prepare the compounds of Examples 221-230 and separated as described in Example 275 above. The absolute configuration of the respective isomers is assigned by will as mentioned above and therefore exchangeable. 5 Example 278 N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl-2 hydroxycyclopentyl}oxy)phenyllacetamide to First eluted isomer. MS-APCI+: m/z 431.1 [MH+]. [a] 22 + 72.2 (CH 2
C
2
)
is Example 279 N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl-2 hydroxycyclopentyl}oxy)phenyllacetamide Second eluted isomer. 20 MS-APCI+ : m/z 431.1 [MH+]. [a] 22 = - 51.4 (CH 2
C
2 ). The diastereomers of Examples 280 and 249 were prepared by methods analogous to those 25 used to prepare the compounds of Examples 221-230 and separated as described in Example 275 above. The compound of Example 280 is the first eluted isomer whilst the compound of Example 249 is the second eluted isomer. The absolute configuration of the respective isomers is assigned by will as mentioned above and therefore exchangeable. 30 Example 280 WO 01/62728 PCT/SEO1/00403 157 N-15-Chloro-2-({(1S,2R,3S)-3-{(3S)-3-(4-chlorophenoxy)pyrrolidinyll-2 hydroxycyclopentyl}oxy)phenyl]acetanide MS-APCI+: m/z 464.9 [MH+]. 5 [a]22 = + 53.0 (CH 2
C
2
)
Example 281 N-{5-Chloro-2- [((S,2R,3S)*-3-{[1-(4-chlorobenzyl)-4-piperidinyll amino}-2 hydroxycyclopentyl)oxy]phenyl}acetamide(racemic mixture) 10 Was prepared by analogy to Example 271 from N-{5-chloro-2-[((R,2S,5R)*-6 oxabicyclo[3.1.0]hex-2-yloxy]phenyl} acetamide (5.3 mg, 20 pLmol) and 1-(4 chlorobenzyl)-4-piperidinamine (4.5 mg, 20 pLmol). 15 MS-APCI+: m/z 492 [M+]. Example 282 N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl-2-hydroxypropyl}oxy)-4 hydroxyphenyllacetamide 20 i) (2S)-2-[(5-Methoxy-2-nitrophenoxy)methylloxirane The subtitle compound was prepared under Mitsunobu conditions from R-(+)-glycidole (198mg, 1mmol), 5-methoxy-2-nitrophenol (169mg, 1mmol), triphenylphosphine (263mg, Immol) and DEAD (157pL, Immol) using dry THF as solvent. The crude material was 25 purified by flashchromatography on silica using mixtures of ethylacetate and heptane as mobile phase. The appropriate fractions were pooled to give impure product as white crystals (175mg). The product was contaminated with reduced DEAD in molar ratio 1:1, which is equal to a yield of the desired product of 100mg, 44%. 30 'H-NMR (400MHz, CDC1 3 ): 6 8.00 (d, 1H); 6.60 (d, 1H); 6.55 (dd, 1H); WO 01/62728 PCT/SEO1/00403 158 6.4 (bs, 1H, red.DEAD); 4.41 (dd, IH); 4.22 (q, 4H, red.DEAD); 4.13 (dd, IH); 3.89 (s, 3H); 3.44-3.39 (m, 1H); 2.95 (dd, 1H); 2.92 (dd, lH); 1.29 (t, 6H, red.DEAD) APCI-MS: m/z 226 [MH*] 5 H) (2S)-1-{(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-3-(5-methoxy-2-nitrophenoxy)-2 propanol The subtitle compound was prepared by analogy to Example I (ii) from (i) (169mg, 0.43mg) and (3S)-3-(4-chlorophenoxy)pyrrolidine (85mg, 0.43mmol). The 10 product was obtained as a yellow oil and was used without further purification. APCI-MS: m/z 423, 425 [MH*] iii) (2S)-1-(2-Amino-5-methoxyphenoxy)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2 is propanol The subtitle compound was prepared in analogy of Example 253 iii) from (ii) (0.43mmol). The product obtained (colourless oil, 163mg) was a mixture of the desired product and reduced DEAD in molar ratio 5:1. The substance was used as it was. 20 1 H-NMR (400MHz, CDCl 3 ): 8 7.23 (d, 2H); 6.77 (d, 2H); 6.67 (d, 1H); 6.49 (d, 1H); 6.41 (bs, red.DEAD); 6.39 (dd, 1H); 4.83-4.77 (m, 1H); 4.22 (q, red.DEAD); 4.14-4.07 (m, 1H); 4.01 (d, 2H); 3.75 (s, 3H); 3.01-2.91 (m, 2H); 2.88-2.72 (m, 3H); 2.62 (dd, iH); 2.29 (hex, 1H); 2.06-1.96 (m, 1H); 1.29 (t, red.DEAD) 25 APCI-MS: m/z 393, 395 [MH*] iv) N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyll-2-hydroxypropyl}oxy)-4 methoxyphenyllacetamide To a solution of compound iii) (157mg) in a mixture of acetonitrile (10mL) and water 30 (2mL) acetic anhydride (1 mL) was added and the mixture was stirred at ambient WO 01/62728 PCT/SEO1/00403 159 temperature overnight. 1.5M sodiummethoxid in methanol (I mL) was added and the stirring continued for 1 h. After evaporation the residue was taken up in ether and water. The subtitle product was obtained from the organic phase as a colourless oil (155mg). 5 'H-NMR (400MHz, CDC1 3 ): 6 8.18 (d, 1H); 7.95 (bs, 1H); 7.24 (d, 2H); 6.78 (d, 2H); 6.56-6.52 (m, 2H); 4.85-4.78 (m, 1H); 4.22 (q, red.DEAD); 4.10-4.02 (m, 2H); 4.00-3.92 (m, 1H); 3.78 (s, 3H); 3.00-2.91 (m, 2H); 2.87-2.73 (m, 3H); 2.53 (dd, 1H); 2.36 2.25 (m, 1H); 2.17 (s, 3H); 2.07-1.99 (m, 1H); 1.29 (t, red.DEAD) 1o APCI-MS: m/z 435, 437 [MH*] v) )-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4 hydroxyphenyllacetamide The title compound was prepared by analogy to Example 254 from iv) (150mg). is The'product obtained after lyophilization was a white amorphous solid (101mg, 57%). 'H-NMR (400MHz, CDCl 3 +1 drop DMSO-d 6 ): 6 8.7 (bs, 1H); 8.34 (s, 1H); 8.73 (d, 1H); 7.18 (d, 2H); 6.73 (d, 2H); 6.40-6.31 (m, 2H); 4.99-4.93 (m, 1H); 4.4-1.9 (bm, 6H); 4.31-4.23 (m, 1H); 3.88-3.78 (m, 2H); 3.39-3.25 (m, 2H); 20 2.4-2.2 (m, 2H); 2.07 (s, 3H) APCI-MS: m/z 421, 423 [MH*] THP-1 Chemotaxis Assay 25 Introduction The assay measured the chenotactic response elicited by MIP- 1 cl chemokine in the human monocytic cell line THP-1. The compounds of the Examples were evaluated by their ability to depress the chemotactic response to a standard concentration of MIP- 1 a 30 chemokine.
WO 01/62728 PCT/SEO1/00403 160 Methods Culture of THP-1 cells Cells were thawed rapidly at 37'C from frozen aliquots and resuspended in a 25 cm flask 5 containing 5 ml of RPMI- 1640 medium supplemented with Glutamax and 10% heat inactivated fetal calf serum without antibiotics (RPMI+ 10%HIFCS). At day 3 the medium is discarded and replaced with fresh medium. THP- 1 cells are routinely cultured in RPMI- 1640 medium supplemented with 10% heat 10 inactivated fetal calf serum and glutamax but without antibiotics. Optimal growth of the cells requires that they are passaged every 3 days and that the minimum subculture density is 4x10+5 cells/ml. Chemotaxis assay is Cells were removed from the flask and washed by centrifugation in RPMI+10%HIFCS+glutamax. The cells were then resuspended at 2x10+7 cells/ml in fresh medium (RPMI+10%HIFCS+glutamax) to which was added calcein-AM (5 p1 of stock solution to 1 ml to give a final concentration of 5x10-6 M). After gentle mixing the cells were incubated at 37*C in a CO 2 incubator for 30 minutes. The cells were then 20 diluted to 50 ml with medium and washed twice by centrifugation at 400xg. Labelled cells were then resuspended at a cell concentration of 1x10+7 cells/ml and incubated with an equal volume of MIP-la antagonist (10~10M to 10-6M final concentration) for 30 minutes at 37*C in a humidified CO 2 incubator. 25 Chemotaxis was performed using Neuroprobe 96-well chemotaxis plates employing 8 pIm filters (cat no. 101-8). Thirty microlitres of chemoattractant supplemented with various concentrations of antagonists or vehicle were added to the lower wells of the plate in triplicate. The filter was then carefully positioned on top and then 25pl of cells preincubated with the corresponding concentration of antagonist or vehicle were added to 30 the surface of the filter. The plate was then incubated for 2 hours at 37'C in a humidified WO 01/62728 PCT/SEO1/00403 161
CO
2 incubator. The cells remaining on the surface were then removed by adsorption and the whole plate was centrifuged at 2000 rpm for 10 minutes. The filter was then removed and the cells that had migrated to the lower wells were quantified by the fluorescence of cell associated calcein-AM. Cell migration was then expressed in fluorescence units after s subtraction of the reagent blank and values were standardized to % migration by comparing the fluorescence values with that of a known number of labelled cells. The effect of antagonists was calculated as % inhibition when the number of migrated cells were compared with vehicle.

Claims (13)

1. A compound of general formula Ra OH RR R 4 R6 sR R (I,) wherein, R represents a group (R)m X 2N m is 0, 1, 2 or 3; to each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C 3 -C 6 cycloalkyl, C-C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C-C 6 haloalkyl, C-C 6 haloalkoxy, -NR 9 R 10 , C 3 -C 6 cycloalkylamino, Ci-C 6 alkylthio, C-C 6 alkylcarbonyl, C-C 6 alkylcarbonylamino, sulphonamido, C 1 -C 6 alkylsulphonyl, -C(O)NR1 R 12, -NR 13C(O)-(NH),R , phenyl, or C 1 -C 6 alkyl optionally substituted by is carboxyl or CrC 6 alkoxycarbonyl; p is 0 or 1; X represents an oxygen or sulphur atom or a CH 2 , CH(CH 3 ), OCH 2 , CH 2 0, CH 2 NH, NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH 2 0, CH 2 NH or NH group, then 20 Y represents a CH group; ZI represents a bond or a group (CH 2 )q where q is 1 or 2; Z2 represents a bond or a group CH 2 , with the proviso that Z and Z2 do not both simultaneously represent a bond; Q represents an oxygen or sulphur atom or a group CH 2 or NH; 25 R2 represents a group WO 01/62728 PCT/SEO1/00403 163 R 15 (R )t n is 0, 1 or 2; s each R3 independently represents a C 1 -C 6 alkyl, CI-C 6 alkoxycarbonyl, -CH 2 OH or carboxyl group; R 4 , R', R 6 and R 7 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group, or R , R5, R6 and R7 together represent a CI-C 4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, 5 6 7 4 8 10 or R., R6 and R each represent a hydrogen atom and R and R together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle; R8 represents a hydrogen atom, a CI-C 6 alkyl group or is linked to R4 as defined above; R9 and R10 each independently represent a hydrogen atom or a Ci-C 6 alkyl group, or 15 R 9 and R together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; RII and R each independently represent a hydrogen atom or a C 1 -C 6 alkyl group optionally substituted by CI-C 6 alkoxycarbonyl; R13 represents a hydrogen atom or a C 1 -C 6 alkyl group; 20 R represents a hydrogen atom, or a Ci-C 6 alkyl group optionally substituted by carboxyl, C 1 -C 6 alkoxy or CI-C 6 alkoxycarbonyl; R15 represents carboxyl, CI-C 6 alkylcarbonyl, CI-C 6 alkoxycarbonyl, Ci-C 6 alkoxycarbonylCI-C 6 alkyl or a group -NR1 R , -NHSO 2 CH 3 , -NHC(O)CH 3 , 17 18 17 18 17 1817 18 -C(O)NR R , -NHC(O)NR R , -OC(O)NR R", -OCH 2 C(O)NR R 25 -NHC(O)OR17' or -OR 1"; t is 0, 1, 2 or 3; WO 01/62728 PCT/SEO1/00403 164 each R16 independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C 3 -C 6 cycloalkyl, C-C 6 alkoxy, C-C 6 alkoxycarbonyl, C-C 6 haloalkyl, C 1 -C 6 haloalkoxy, -NR1 R20, C 3 -C 6 cycloalkylamino, C-C 6 alkylthio, C-C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, sulphonamido (-SO 2 NH 2 ), S C-C 6 alkylsulphonyl, -C(O)NR21 R, -NR C(O)(NH),R 24, phenyl, or C -C 6 alkyl optionally substituted by carboxyl or C 1 -C 6 alkoxycarbonyl; R 17 and R18 each independently represent (i) a hydrogen atom, (ii) a 5- to 6 membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at 1o least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a C-C 6 alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C 1 -C 6 alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one is substituent selected from halogen, methyl and trifluoromethyl, or R 7 and R18 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; R represents a hydrogen atom, or a C-C 6 alkyl group optionally substituted by carboxyl or C -C 6 alkoxycarbonyl; 20 R is defined as for R above except that R does not represent a hydrogen atom; R 9 and R20 each independently represent a hydrogen atom or a CI-C 6 alkyl group, or R19 and R20 together with the nitrogen atom to which they are attached form a 4- to 7 membered saturated heterocycle; R21 and R each independently represent a hydrogen atom or a C 1 -C 6 alkyl group 25 optionally substituted by C 1 -C 6 alkoxycarbonyl; v is 0 or 1; R23 represents a hydrogen atom or a C-C 6 alkyl group; and R24 represents a hydrogen atom, or a C-C 6 alkyl group optionally substituted by carboxyl, C-C 6 alkoxy or Cr-C 6 alkoxycarbonyl; 30 or a pharmaceutically acceptable salt or solvate thereof WO 01/62728 PCT/SEO1/00403 165
2. A compound according to claim 1, wherein X represents an oxygen atom or a CH2, OCH 2 , CH 2 0, NH or carbonyl group. 5 3. A compound according to claim 1 or 2, wherein Y represents a nitrogen atom or CH group.
4. A compound according to any one of claims 1 to 3, wherein Q represents an oxygen atom. 10
5. A compound according to any one of claims I to 4, wherein R 15 represents C 1 -C 4 alkoxy, CI-C 4 alkylcarbonyl, CI-C 4 alkoxycarbonylCi-C 4 alkyl, -NHC(O)CH 3 , 17 18 17 18 -C(O)NR R1, -NHSO 2 CH 3 or -NHC(O)NR R is 6. A compound according to any one of claims 1 to 5, wherein each R16 independently represents halogen, cyano, hydroxyl, Ci-C 4 alkoxy, Ci-C 4 alkoxycarbonyl, C 1 -C 4 haloalkyl, Ci-C 4 alkylcarbonyl, phenyl or CI-C 4 alkyl.
7. A compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, 20 as defined in claim 1 being selected from: N-(2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl) acetamide hydrochloride, N-(5-Chloro-2- { 3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1 -yl]-2R,S-hydroxy propoxy} -phenyl)-acetamide hydrochloride, 25 N-(2- {3-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]-2-hydroxypropoxy}phenyl) acetamide, 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol dihydrochloride, N-(2- {3-[3-(3,4-dichlorophenoxy)- 1 -pyrrolidinyl)-2-hydroxypropoxy} phenyl) 30 acetamide hydrochloride, WO 01/62728 PCT/SEO1/00403 166 2-{3-[4-(4-Fluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -benzoic acid methyl ester, 2-(2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester, 5 N-[2-({(IR,2S,3R)*-3-[4-(3,4-dichlorophenoxy)- I -piperidinyl)-2 hydroxycyclopentyl} oxy)phenyl]acetamide, N-[2-({(lS,2S,3R)*-3-[4-(3,4-dichlorophenoxy)- -piperidinyl)-2 hydroxycyclopentyl} oxy)phenyl]acetamide, N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)- 1 -piperidinyl]-2 10 hydroxycyclohexyl} oxy)phenyl]acetamide, N-(5-Chloro-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(3-Acetyl-2- {3-[3-(3,4-dichloro-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, 15 N-(2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, N-(2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, N-(4- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -biphenyl-3 20 yl)-acetamide, N-(2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, N-(2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamide, 25 N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, N-(5-Chloro-2- {3-[3-(4-chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(3-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5 30 methyl-phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 167 N-(2- {3-[3 -(4-Chloro-phenoxy)-pyrrolidin- l-yl] -2-hydroxy-propoxy} -4-methyl phenyl)-acetamTide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, 5 N-(4- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -biphenyl-3 -yl) acetamide, N-(2- {3-[3 -(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, N-(2- {3 -[3 -(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -5-methyl 10 phenyl)-acetamnide, N-(2-{3- [3 -(4-Chloro-phenoxy)-pyrrolidin- 1-yll-2-hydroxy-propoxy} -phenyl) acetamnide -N-(5-Chloro-2-1{3 -[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy } phenyl)-acetamide, 15 N-(3-Acetyl-2- {3 -[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yll-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, N-(2- {3-[3 -(4-Fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, N-(5-Fluoro-2- {3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]l-2-hydroxy-propoxy} 20 phenyl)-acetamide, N-(4- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -biphenyl-3-yl) acetamide, N-(4-Fluoro-2- {3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1-yl]f-2-hydroxy-propoxy} phenyl)-acetamide, 25 N-(2- {3-[3 -(4-Fluoro-phenoxy)-pyrrolidin-1I-yI]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamnide, N-(2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -phenyl) acetamide, N-(5-Chloro-2- {3-[3-(3 ,4-difluoro-phenoxy)-pyrrolidin- 1-yl j-2-hydroxy-propoxy} 30 phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 168 N-(3-Acetyl-2- {3-[3-(3 ,4-difluoro-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy} -5. methyl-phenyl).-acetamide, N-(2- {3)-[3 -(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, 5 N-(2- {3 -[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl],-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, N-(4-{3 -[3-(3 ,4-Difluoro-phenoxy)-pynrolidin- 1 -yl j-2-hydroxy-propoxy} -biphenyl-3 yl)-acetamide, N-(2- {3-[3 -(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -ylI-2-hydroxy-propoxy} -4-fluoro 10 phenyl).-acetamide, N-(2- {3 -[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamnide, N-(2- {3 -[3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy-propoxy} -phenyl) acetamnide, 15 N-(5-Chloro-2- {3-[4-(3 ,4-dichloro-phenoxy)-piperidin- 1-yl j-2-hydroxy-propoxy} phenyl)-acetamnide, N-(3-Acetyl-2- {3-[4-(3 ,4-dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamnide, N-(2- f{3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl 20 phenyl)-acetamide, N-(2- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-.acetamnide, N-(4- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yll-2-hydroxy-propoxy} -biphenyl-3 yl)-acetamide, 25 N-(2- {3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, N-(2- {3- [4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy}j -5-methyl phenyl)-acetamide, N-(2- {3 -[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 30 acetamide, WO 01/62728 PCT/SEO1/00403 169 N-(5-Chloro-2-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(3-Acetyl-2-{3-[4-(4-chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5 methyl-phenyl)-acetamide, 5 N-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -4-methyl phenyl)-acetamide, N-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -5-fluoro phenyl)-acetamide, N-(4-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -biphenyl-3-yl) to acetamide, N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy} -4-fluoro phenyl)-acetamide, N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -5-methyl phenyl)-acetamide, is N-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 3-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) 20 propionic acid methyl ester, 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol, 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy}-N,N-dimethyl benzamide, 25 1-(2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy}-phenyl) propan- I-one, 1-(2- {3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1-yl] -2 -hydroxy-propoxy} -phenyl) ethanone, 3-(2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 30 propionic acid methyl ester, WO 01/62728 PCT/SEO1/00403 170 1-(2,6-Dimethoxy-phenoxy)-3-[3-(4-fluoro-phenoxy)-pyrrolidin- 1 -yl]-propan-2-ol, 1-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol, (2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}-benzoylamino) acetic acid methyl ester, 5 (2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} benzoylamino)-acetic acid methyl ester, 2-(2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin-I -yl]-2-hydroxy-propoxy} -benzoylamino) 2-methyl-propionic acid methyl ester, 2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy}-N,N-dimethyl 10 benzamide, . 1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy phenyl)-ethanone, 1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan 1-one, is 1-(2- {3-[3-(4-Fluoro-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy} -phenyl) ethanone, N-[2-(3- {[1 -(3,4-dichlorobenzyl)-4-piperidinyl]amino }-2-hydroxypropoxy)-4 methylphenyl]acetamide, 3-(2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 20 propionic acid methyl ester, 1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- I-yl]-3-(2-methoxy-phenoxy)-propan-2-ol, (2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} benzoylamino)-acetic acid methyl ester, 2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl 25 benzamide, 1-(2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -6-methoxy phenyl)-ethanone, 1-(2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propan- 1-one, WO 01/62728 PCT/SEO1/00403 171 1-(2- {3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, N-(2- {3-[4-(3,4-dichloroanilino)- 1 -piperidinyl]-2-hydroxypropoxy}phenyl)acetamide, 3-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}-phenyl) 5 propionic acid methyl ester, 1-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]- 3 -(2,6-dimethoxy-phenoxy)-propan-2-ol, 1-[3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol, (2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin-1 -yl]-2-hydroxy-propoxy} -benzoylamino) acetic acid, methyl ester, 10 2-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy}-benzoylamino) 2-methyl-propionic acid methyl ester, 2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- I -yl]-2-hydroxy-propoxy} -6-methoxy is phenyl)-ethanone, 1-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl)-propan 1-one, 1-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, 20 N-(2- {3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 3-(2- {3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, (2- {3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino) 25 acetic acid methyl ester, 2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 4- { 1-[2-Hydroxy-3 -(2-propionyl-phenoxy)-propyl]-pyrrolidin-3 -yloxy} -benzonitrile, N-(2- {2-Hydroxy-3-[3-(4-methoxy-phenoxy)-pyrrolidin- 1 -yl]-propoxy} -phenyl) 30 acetamide, WO 01/62728 PCT/SEO1/00403 172 N-(4-chloro-2- {3-[4-(3,4-dichloroanilino)- 1 -piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, 3-(2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 5 1 -[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]- 3 -(2-methoxy-phenoxy)-propan-2-ol, (2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} benzoylamino)-acetic acid methyl ester, 2-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester,
10. 2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -6-methoxy phenyl)-ethanone, 1'-(2-{3 -[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 15 propan-1-one, 1-(-2- {3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy }-phenyl) ethanone, N-(2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 20 3-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) 25 propan-1-one, (2- {3-[4-(3,4-Difluoro-phenoxy)-piperidin-1 -yl]-2-hydroxy-propoxy} -benzoylamino) acetic acid methyl ester, N-(2- {3-[3-(3,4-Difluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 173 N-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 3-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -phenyl)-propionic acid methyl ester, s 1-(2,6-Dimethoxy-phenoxy)-3-[4-(4-fluoro-phenoxy)-piperidin- 1 -yl]-propan-2-ol, 1-[4-(4-Fluoro-phenoxy)-piperidin-1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 1-(2- {3-[4-(4-Fluoro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -phenyl)-ethanone, 2- {3-[4-(4-Fluoro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, to 1-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan 1-one, (2- {3-[4-(4-Fluoro-phenoxy)-piperidin- I -yl]-2-hydroxy-propoxy} -benzoylamino) acetic acid methyl ester, N-(2- {3-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) is acetamide, . 3-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl) propionic acid methyl ester, 1-[3-(4-Fluoro-phenoxymethyl)-piperidin-1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 1-(2- {3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1 -yl]-2-hydroxy-propoxy} -phenyl) 20 ethanone, 2-(2- {3-[3-(4-Fluoro-phenoxymethyl)-piperidin- 1-yll-2-hydroxy-propoxy} benzoylamino)-2-methyl-propionic acid methyl ester, 2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1 -yl]-2-hydroxy-propoxy}-N,N dimethyl-benzamide, 25 1-(2-f{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy} -6 methoxy-phenyl)-ethanone, N-(2-{3-[4-(4-Acetylamino-phenoxy)-piperidin-I -yl]-2-hydroxy-propoxy} -phenyl) acetamide, N-(4-{1-[3-(2-Acetyl-phenoxy)-2-hydroxy-propyl]-piperidin-4-yloxy}-phenyl) 30 acetamide, WO 01/62728 PCT/SEO1/00403 174 N-(4-cyano-2-{3-[4-(3,4-dichloroanilino)- 1 -piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, 3-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 5 1-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-3-(2-methoxy-phenoxy)-propan-2-ol, 1-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, 2-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -benzoylamino)-2 methyl-propionic acid methyl ester, 10 2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N-dimethyl benzamide, 1-(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -6-methoxy phenyl)-ethanone, 1 -(2- {3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl)-propan is 1-one, (2-{3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy- propoxy} -benzoylamino) acetic acid methyl ester, N-(2- {3-[3 -(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) acetamide, 20 3-(2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propionic acid methyl ester, 1-(2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) ethanone, 2- {3-[3-(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -N,N 25 dimethyl-benzamide, 1-(2- {3-[3 -(4-Chloro-phenoxymethyl)-piperidin- 1 -yl]-2-hydroxy-propoxy} -phenyl) propan-1-one, N-[2-({(1R,2R)-2-[4-(3,4-dichlorophenoxy)- 1 -piperidinyl]- 1 hydroxycyclopentyl}methoxy)phenyl]acetamide, WO 01/62728 PCT/SEO1/00403 175 Methyl (2S,4R)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-[(4 chlorobenzyl)oxy]-2-pyrrolidinecarboxylate hydrochloride, N-(2- {3-[4-(3,4-Dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4 methylphenyl)acetamide, 5 N-(2- {3-[4-(4-Chloroanilino)-1 -piperidinyl]-2-hydroxypropoxy}phenyl)acetamide, N-(4-Chloro-2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl) acetamide, N-(2-{3-[4-(4-Chloroanilino)- 1 -piperidinyl]-2-hydroxypropoxy} -4 cyanophenyl)acetamide, 10 N-(2- {3-[4-(4-Chloroanilino)- 1 -piperidinylj-2-hydroxypropoxy} -4 methylphenyl)acetamide, N-(5-Chloro-2- {3-[4-(4-fluoroanilino)- I -piperidinyl]-2 hydroxypropoxy} phenyl)acetamide, N-(5-Chloro-2- {3-[4-(3,4-difluoroanilino)- 1 -piperidinyl]-2 1s hydroxypropoxy}phenyl)acetamide, N-(5-Cyano-2-{3-[4-(4-fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy} -: phenyl)acetamide, N-(5-Cyano-2-{3-[4-(3,4-difluoroanilino)-1-piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, 20 N-(2- {3-[4-(4-Fluoroanilino)- I -piperidinyl]-2-hydroxypropoxy} -4 methylphenyl)acetamide, N-(2- {3-[4-(3,4-Difluoroanilino)- 1 -piperidinyl-2-hydroxypropoxy} -4 methylphenyl)acetamide, N-(2- {3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-(R)-hydroxy-propoxy 25 phenyl)acetamide, N-(2-{3-[3S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2S-hydroxy-propoxy}-phenyl) acetamide hydrochloride, N-(2- {3-[3(R)-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-(S)-hydroxy-propoxy phenyl)acetamide, WO 01/62728 PCT/SEOI/00403 176 N-[5-Chloro-2-( {(2S)-3-[(3 S)-3-(4-chloro-phenoxy)pyrrolidinylj-2 hydroxypropyl I oxy)phenyl]acetamide, N-[5-Chloro-2-( {(2R)-3 -[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl}I oxy)phenyllacetamnide, 5 N-[5-Chloro-2-( {(2S)-3-[(3R)-3 -(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl} oxy)phenyl]acetamide, N-[5-Chloro-2-( {(2R)-3-[(3 S)-3 -(4-chloro-phenoxy)pyrrolidinyl]-2 hydroxypropyl} oxy)phenyl]acetamide, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} -4,5-difluoro 10 phenyl)-acetamide, N-f 5-Chloro-2-[2-hydroxy-3-(3-phenoxy-pyrrolidin- 1 -yl)-propoxy]-phenyl} acetamide, N-(5-Chloro-2- {2-hydroxy-3-[3-(4-nitro-phenoxy)-pyrrolidin- 1 -yl]-propoxy} -phenyl) acetamide, 15 N-(5-Acetyl-2- {3-[3-(3 ,4-dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} phenyl)-acetamide, 4-Acetylamino-3- {3-[3-(3 ,4-dichloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} benzoic acid methyl ester, N-(2- {3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -y1l-2-hydroxy-propoxy} -5-cyano 20 phenyl)-acetamide, 4-Acetylamnino-3- {3-[3-(4-chloro-phenoxy)-pyrrolidin- 1 -yll-2-hydroxy-propoxy} benzoic acid methyl ester, N-(5-Cyano-2- f{3-[4-(3 ,4-dichloro-phenoxy)-piperidin- 1 -yll-2-hydroxy-propoxy} phenyl)-acetamide, 25 N-(2-1{3-[4-(3 ,4-Dichloro-phenoxy)-piperidin- 1-yl]-2-hydroxy-propoxy} -5 trifluoromethyl-phenyl)-acetamide, N-(5-Chloro-2- {3-[3-(4-fiuoro-phenoxy)-pyrrolidin- 1-yI-2-hydroxy-propoxy} phenyl)-acetamide trifluoroacetate, N-(5-Acetyl-2- {3-[3 -(4-chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy} 30 phenyl)-acetamide trifluoroacetate, WO 01/62728 PCT/SEO1/00403 177 N-(2- { 3-[3-(4-Chlorophenoxy)- 1 -pyrrolidinyl]-2-hydroxypropoxy}phenyl) methanesulfonamide, N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)- 1 -pyrrodinyl]-2-hydroxypropoxyj phenyl)urea, 5 1-(3- {2-[(Aminocarbonyl)amino]phenoxy} -2-hydroxypropyl)-3-(4 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate, 1-(3- {2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4 dichlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate, 1-(3- {2-[(Aminocarbonyl)amino]-4-chlorophenoxy} -2-hydroxypropyl)-3-(4 10 chlorophenoxy)pyrrolidinium 2,2,2-trifluoroacetate, N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N ethylurea hydrochloride, N-(2- {3-[3-(4-Chlorophenoxy)-1 -pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N methylurea hydrochloride, is (2S,4S)- 1- {3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2 pyrrolidinecarboxylic acid; compound with trifluoroacetic acid, Ethyl (2S,4S)- 1- {3-[2-(acetylamino)phenoxyl-2-hydroxypropyl } -4-(3,4 dichlorophenoxy)-2-pyrrolidinecarboxylate; trifluoroacetic acid salt, N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2 20 hydroxypropyl}oxy)phenyl]acetamide; trifluoroacetic acid salt, N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2 hydroxypropyl}oxy)phenyl]acetamide; trifluoroacetic acid salt, N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2 methylpropoxy}phenyl)acetamide hydrochloride, 25 N-(2-{(1S,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy cyclopentyloxy}-phenyl)-acetamide, N-(2-{(lR*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin- -yl]-2-hydroxy cyclopentyloxy} -phenyl)-acetamide, N-(2- {(2R*,3R*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-butoxy} 30 phenyl)-acetamide, WO 01/62728 PCT/SEO1/00403 178 N-(2- {(lS*,2R*,3S*)-3-[4-(4-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy cyclopentyloxy} -phenyl)-acetamide, N-(2- { (2R*,3S)-3 -[4-(3,4-Dichloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy-butoxy} phenyl)-acetamide, 5 N-(2- { (2R,3R)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl] -2-hydroxy-butoxy} phenyl)-acetamide, N-(2-(2R*,3S)-3-[3-(4-Chloro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy-butoxy} phenyl)-acetamide, N-(2- {(S*,2R*,3S*)-3-[4-(3-Chloro-phenoxy)-piperidin- 1 -yl]-2-hydroxy 10 cyclopentyloxy} -phenyl)-acetamide, N-[5-Chloro-2-({(1 S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)- 1 -piperidinyl]-2 hydroxycyclopentyl}oxy)phenyl]acetamide, N-[4-Fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2 hydroxycyclopentyl}oxy)phenyl]acetamide, is N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-phenyl)acetamide dihydrochloride, N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-4 fluorophenyl)acetamide, N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2 20 hydroxypropoxy}phenyl)acetamide, N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinyl]-2 hydroxypropoxy}phenyl)acetamide, N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2 hydroxypropoxy}phenyl)acetamide, 25 N-(2- {3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2-hydroxypropoxy} -4 methylphenyl)acetamide, N-(2- {3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2-hydroxypropoxy} -4 fluorophenyl)acetamide, N-(2-{3 [(S*R*)-4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2 30 hydroxypropoxy}phenyl)acetamide, WO 01/62728 PCT/SEO1/00403 179 N-(2- {3 [(S *R*)-4(4-Chlorobenzy1>-2,5-dimethyb I -piperazinyl]-2 hydroxypropoxy} phenyl)acetamide, N-(5-Chloro-2- {3-.[(S*R *).4.{3 ,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2 hydroxypropoxy} phenyl)acetamnide, 5 N-(5-Chloro-2- {3-.[(S*R *)-4(4chorobeny)25dimethylpiperaziny]i2. hydroxypropoxy} phenyl)acetamnide, 1 -(5-Chloro-2- f 3-[4-(4-chlorobenzoyl)- I -piperazinyl]-2-hydroxypropoxy} phenyl)- 1 ethanone, N-(5-Cyano-2- { 3-[(S*R *}..4.(3 ,4-dichlorobenzyl)-2,5-dimethylpiperazinyl-2 t0 hydroxypropoxylphenyl)acetamnide, N-(2- {3 -[(S*R *>-4.(4-Chlorobenzyl).2,5-dimethylpiperazinyl]2-hydroxypropoxyI -5 cyanophenyl)acetamide, .N-(5-Chloro-2- {3-[4-(4-chlorobenzyl)- 1-piperazinyl]-2-hydroxypropoxy} phenyl)acetamide, 15 N-(4-Chloro-2- {3-[4-(4-chlorobenzyl)-2,5-dimethyl- 1 -piperazinyl]-2 hydroxypropoxy} phenyl)acetamide, N-(2- f 3 -[4-(4-Chlorobenzoyl)- 1 -piperazinyl]-2-hydroxypropoxy} -5 cyanophenyl)acetarnide, N-(2- {3 -[4-(4-Chlorobenzoyl)- 1 -piperazinyll-2-hydroxypropoxy} -4 20 methlylphenyl)acetamnide, N-[5-Chloro-2-( {( 1R,2S,3R)-3-[(38'J-3 -(4-chlorophenoxy)pyrrolidinyl]-2 hydroxycyclopentyl} oxy)phenyl]acetamide, N- {2-[(2S)-(3- {(3 S)-.3-[(4-Chlorophenyl)oxy]- 1 -pyrrolidiriyl } -2-hydroxypropyl)oxy] 4-fluorophenyl}I acetamide, 25 N-[2-( {(25S)-3-[(3S)-3-(4-Chlorobenzyl)pyrrolidinyl]-2- hydroxypropyl} oxy)phenyl]acetamnide hydrochloride, N-(5-Chloro-2-1{3-[3-(4-chloro-benzyl)-pyrrolidin-l1-yI]-2-hydroxy-propoxy} -phenyl) acetamide trifluoroacetic acid salt, N-(2- {3-[3-(4-Chlorophenoxy)-l1-pyrrolidinyl]-2-hydroxypropoxy} -4-methyiphenyl) 30 1 -pyrrolidinecarboxamide trifluoro acetate, WO 01/62728 PCT/SEO1/00403 180 N-(2- {3-[3-(4-Chlorophenoxy)- 1 -pyrrolidinyl]-2-hydroxypropoxy} -4 hydroxyphenyl)acetamide trifluoroacetate, N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]-2-hydroxypropyl}oxy)-4 fluorophenyl]acetamide trifluoroacetic acid salt, s N-(2-(3-(4-Chloro-phenoxy)-pyrrolidin-1-yl)-2-hydroxy-propoxy)-4,6-difluoro phenyl)-acetamide hydrochloride, N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2 hydroxypropyl}oxy)-4-fluorophenyl]acetamide trifluoroacetic acid salt, N-[2-({(2S)-3-[(3R)-3-(4-Chlorobenzyl)pyrrolidinyl]-2 10 hydroxypropyl} oxy)phenyl] acetamide hydrochloride, N-{2-[(2R)- (3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy] 4-fluorophenyl } acetamide, N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2 hydroxypropyl}oxy) phenylacetamide trifluoroacetic acid salt, 15 N-{2-[(2S)-(3-{(3R)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy] 4-fluorophenyl} acetamide, N-(2-{3-[3-(4-Chlorophenoxy)- 1 -pyrrolidinyl]-2-hydroxypropoxy} -4-methylphenyl) N,N-dimethylurea trifluoroacetate, N-(2- {3-[3-(4-Chloroanilino)-1 -pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide, 20 N- {2-[(3- {3-[(4-Chlorophenyl)oxy]- 1-pyrrolidinyl}-2-hydroxy- 1 methylpropyl)oxy]phenyl}acetamide hydrochloride, N-(2- {3-[3-(4-Chlorophenoxy)-1 -pyrrolidinyl]-2-hydroxypropoxy}-4 methoxyphenyl)acetamide hydrochloride, N-(2-[3-(4-Chloro-benzyloxy)-pyrrolidin- 1 -yl]-2-hydroxy-propoxy)-phenyl) 25 acetamide trifluoroacetic acid salt, N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl)-2-hydroxy-2-methyl-propoxy} phenyl)-acetamide, N-(2- {(l S,2R,3S)*-3-[(3S)-3-(3 ,4-Difluoro-phenoxy)-pyrrolidin- 1 -yl]-2-hydroxy cyclopentyloxy}-5-chloro-phenyl)-acetamide (diastereomeric mixture), WO 01/62728 PCT/SEO1/00403 181 N-[2-({(2R,3S) *-3-[(3S)- -(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxybutyl oxy)-4 methylphenyl]acetamide (diastereomeric mixture), N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl} -2-hydroxy-2 methylpropyl)oxy]-4-fluorophenyl}acetamide hydrochloride, 5 N-(2- {(S,2R,3S)*-3-[(S)-3-(4-Chloro-phenoxy)-pyrrolidin- 1-yl]-2-hydroxy cyclopentyloxy}-4-fluoro-phenyl)-acetamide (diastereomeric mixture), N-(5-Chloro-2-f{3-[3-(3 ,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} phenyl)-acetamide, N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} 10 phenyl)-acetamide, N-(4-Cyano-2-{ 3-[4-(3 ,4-dichloroanilino)-1-piperidinyl]-2 hydroxypropoxy}phenyl)acetamide, N-(4-Hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 hydroxy-cyclopentyloxy}-phenyl)-acetamide (diastereomeric mixture), 15 N-(4-Hydroxy-2-{(1S,2R,3S)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2 hydroxy-cyclopentyloxy} -phenyl)-acetamide, N-(4-Hydroxy-2- {(lR,2S,3R)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin- 1 -yl]- 2 hydroxy-cyclopentyloxy} -phenyl)-acetamide, N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2 20 hydroxycyclopentyl} oxy)phenyl]acetamide, N-[2-({(lR,2S,3R)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2 hydroxycyclopentyl}oxy)phenyl]acetamide, N-[5-Chloro-2-({(IS,2R,3S)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2 hydroxycyclopentyl}oxy)phenyl]acetamide, 25 N-{5-Chloro-2-[((IS,2R,3S)*-3-{[1-(4-chlorobenzyl)-4-piperidinyl] amino}-2 hydroxycyclopentyl)oxy]phenyl} acetamide (racemic mixture), and N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4 hydroxyphenyl]acetamide. WO 01/62728 PCT/SEO1/00403 182 8. A process for the preparation of a compound of formula (I') as defined in claim I which comprises, (a) reacting a compound of general formula R-H (II') 5 wherein R is as defined in formula (I'), with a compound of general formula 0 RQ R 7 R R R (II,) wherein Q, R 2 , Ri, Ri, R6, RI and R 8 are as defined in formula (I'); or (b) reacting a compound of general formula 10 R R 5 R R R (IV') 4 5 67 8 wherein R, R , R , R , R and R are as defined in formula ('), with a compound of general formula is L -Q - R (V') wherein L I represents a hydrogen atom or an activating group and Q and R2 are as defined in formula (I'); and optionally thereafter converting the compound of formula (I') to a further compound of 20 formula (I'); and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I'). 9. A pharmaceutical composition comprising a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 25 in association with a pharmaceutically acceptable adjuvant, diluent or carrier. WO 01/62728 PCT/SEO1/00403 183 10. A process for the preparation of a pharmaceutical composition as claimed in claim 9 which comprises mixing a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 with a pharmaceutically acceptable adjuvant, diluent or carrier. 5
11. A compound of formula (I'), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims I to 7 for use in therapy.
12. Use of a compound of formula (I'), or a pharmaceutically acceptable salt or solvate io thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in therapy.
13. Use of a compound of formula (F), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for the 15 treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.
14. Use of a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use 20 in treating rheumatoid arthritis.
15. Use of a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease. 25
16. Use of a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in treating asthma. WO 01/62728 PCT/SEO1/00403 184
17. Use of a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in treating multiple sclerosis. 5 18. A method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 7. 10 19. A method of treating an airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims I to 7.
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